Bicyclo[3.1.0]hexane containing oxazolidinone antibiotics and derivatives thereof

ABSTRACT

Oxazolidinones having a bicyclic[3.1.0]hexane containing moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci,  Bacteroides  spp.,  Clostridia  spp. species, as well as acid-fast organisms such as  Mycobacterium tuberculosis  and other mycobacterial species. 
 
The compounds are represented by structural formula I:  
                 
 
its enantiomer, diastereomer, or pharmaceutically acceptable salt or ester thereof, and wherein the variables R 1 , R 2 , R 3 , R 4 , R 4a , A, Ar, HAr, n, r, and s are as defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to Provisional Application Ser. No., ______, filed Mar. 14, 2002, and Provisional Application Ser. No. 60/283,956, filed Apr. 17, 2001.

BACKGROUND OF THE INVENTION

Oxazolidinones represent the first new class of antibacterials to be developed since the quinolones. The oxazolidinones are synthetic antibacterial compounds that are orally or intravenously active against problematic multidrug resistant Gram positive organisms and are not cross-resistant with other antibiotics. See Riedl et al, Recent Developments with Oxazolidinone Antibiotics, Exp. Opin. Ther. Patents (1999) 9(5), Ford et al., Oxazolidinones: New Antibacterial Agents, Trends in Microbiology 196 Vol. 5, No. 5, May 1997 and WO 96/35691.

This invention relates to new oxazolidinones having a bicyclic[3.1.0]hexane containing moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as Mycobacterium tuberculosis and other mycobacterial species.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I:

its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof wherein:

-   -   A represents C (when --- is present), CH, or N (when --- is not         present);     -   ---- represents a bond;     -   R represents hydrogen, or C₁₋₆ alkyl;     -   R₁ and R₂ independently represent     -   i) hydrogen,     -   ii) NR₅R₆,     -   iii) CR₇R₈R₉, C(R)₂OR₁₄, CH₂NHR₁₄,     -   iv) C(═O)R₁₃, C(═NOH)H, C(═NOR₁₃)H, C(═NOR₁₃)R₁₃, C(═NOH)R₁₃,         C(═O)N(R₁₃)₂, C(═NOH)N(R₁₃)₂, NHC(═X₁)N(R₁₃)₂, (C═NH)R₇,         N(R₁₃)C(═X₁)N(R₁₃)₂, COOR₁₃, SO₂R₁₄, N(R₁₃)SO₂R₁₄, N(R₁₃)COR₁₄,         or (C₁₋₆alkyl)CN, CN, CN═C(R)₂, OH, C(═O)CHR₁₃, C(═NR₁₃)R₁₃,         NHC(═X₁)R₁₃;     -   vi) C₅₋₁₀ heterocycle optionally substituted with 1-3 groups of         R₇, which may be attached through either a carbon or a         heteroatom;         represents aryl or heteroaryl, heterocycle, heterocyclyl or         heterocyclic,     -   R_(x) represents hydrogen or C₁₋₆ alkyl;     -   R₃ represent     -   i) NH(C═X₂)R₁₂,     -   ii) NHSO₂R₁₄,     -   iii) NH(CH₂)₀₋₄aryl,     -   iv) NH(CH₂)₀₋₄heteroaryl,     -   v) S(CH₂)₀₋₄aryl,     -   vi) S(CH₂)₀₋₄heteroaryl,     -   vii) O(CH₂)₀₋₄aryl, or     -   viii) O(CH₂)₀₋₄heteroaryl;     -   R₄ and R_(4a) independently represent     -   i) hydrogen,     -   ii) halogen,     -   iii) C₁₋₆ alkoxy, or     -   iv) C₁₋₆ alkyl     -   r and s independently are 1-3, with the provision that when         (R_(4a))_(s) and (R₄)_(r) are attached to an Ar or HAr ring the         sum of r and s is less than or equal to 4;     -   R₅ and R₆ independently represent     -   i) hydrogen,     -   ii) C₁₋₆ alkyl optionally substituted with 1-3 groups of         halogen, CN, OH, C₁₋₆ alkoxy, amino, imino, hydroxyamino,         alkoxyamino, C₁₋₆ acyloxy, C₁₋₆ alkylsulfenyl, C₁₋₆         alkylsulfinyl, C₁₋₆ alkylsulfonyl, aminosulfonyl, C₁₋₆         alkylaminosulfonyl, C₁₋₆ dialkylaminosulfonyl,         4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl,         ethylenyloxy, or ethynyl, said phenyl and pyridine optionally         substituted with 1-3 halogen, CN, OH, CF₃, C₁₋₆ alkyl or C₁₋₆         alkoxy;     -   iii) C₁₋₆ acyl optionally substituted with 1-3 groups of         halogen, OH, SH, C₁₋₆ alkoxy, naphthalenoxy, phenoxy, amino,         C₁₋₆ acylamino, hydroxylamino, alkoxylamino, C₁₋₆ acyloxy,         aralkyloxy, phenyl, pyridine, C₁₋₆ alkylcarbonyl, C₁₋₆         alkylamino, C₁₋₆ dialkylamino, C₁₋₆ hydroxyacyloxy, C₁₋₆         alkylsulfenyl, phthalimido, maleimido, succinimido, said         phenoxy, phenyl and pyridine optionally substituted with 1-3         groups of halo, OH, CN, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃         or C₁₋₆ alkyl;     -   iv) C₁₋₆ alkylsulfonyl optionally substituted with 1-3 groups of         halogen, OH, C₁₋₆ alkoxy, amino, hydroxylamino, alkoxylamino,         C₁₋₆ acyloxy, or phenyl; said phenyl optionally substituted with         1-3 groups of halo, OH, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃         or C₁₋₆ alkyl;     -   v) arylsulfonyl optionally substituted with 1-3 of halogen, C₁₋₆         alkoxy, OH or C₁₋₆ alkyl;     -   vi) C₁₋₆ alkoxycarbonyl optionally substituted with 1-3 of         halogen, OH, C₁₋₆ alkoxy, C₁₋₆ acyloxy, or phenyl, said phenyl         optionally substituted with 1-3 groups of halo, OH, C₁₋₆ alkoxy,         amino, C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl;     -   vii) aminocarbonyl, C₁₋₆ alkylaminocarbonyl or C₁₋₆         dialkylaminocarbonyl, said alkyl groups optionally substituted         with 1-3 groups of halogen, OH, C₁₋₆ alkoxy or phenyl     -   viii) five to six membered heterocycles optionally substituted         with 1-3 groups of halogen, OH, CN, amino, C₁₋₆ acylamino, C₁₋₆         alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkoxy, C₁₋₆         acyloxy or C₁₋₆ alkyl, said alkyl optionally substituted with         1-3 groups of halogen, or C₁₋₆ alkoxy;     -   ix) C₃₋₆ cycloalkylcarbonyl optionally substituted with 1-3         groups of halogen, OH, C₁₋₆ alkoxy or CN;     -   x) benzoyl optionally substituted with 1-3 groups of halogen,         OH, C₁₋₆ alkoxy, C₁₋₆ alkyl, CF₃, C₁₋₆ alkanoyl, amino or C₁₋₆         acylamino;     -   xi) pyrrolylcarbonyl optionally substituted with 1-3 of C₁₋₆         alkyl;     -   xii) C₁₋₂ acyloxyacetyl where the acyl is optionally substituted         with amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, 4-morpholino,         4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl; or     -   R₅ and R₆ taken together with any intervening atoms can form a 3         to 7 membered heterocyclic ring containing 1-2 heteroatoms         independently chosen from O, S, SO, SO₂, N, or NR₈;     -   R₇ represent     -   i) hydrogen, halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl, alkenyl,     -   ii) amino. C₁₋₆ alkylamino, C₁₋₆ dialkylamino, hydroxylamino or         C₁₋₂ alkoxyamino all of which can be optionally substituted on         the nitrogen with C₁₋₆ acyl, C₁₋₆ alkylsulfonyl or C₁₋₆         alkoxycarbonyl, said acyl and alkylsulfonyl optionally         substituted with 1-2 of halogen or OH;     -   R₈ and R₉ independently represents     -   i) H, CN,     -   ii) C₁₋₆ alkyl optionally substituted with 1-3 halogen, CN, OH,         C₁₋₆ alkoxy, C₁₋₆ acyloxy, or amino,     -   iii) phenyl optionally substituted with 1-3 groups of halogen,         OH, C₁₋₆ alkoxy; or     -   R₇ and R₈ taken together can form a 3-7 membered ring optionally         interrupted with 1-2 heteroatoms chosen from O, S, SO, SO₂, NH,         and NR₈;     -   X₁ represents I, S, NR₁₃, NCN, or NSO₂R₁₄     -   X₂ represents O, S, NH or NSO₂R₁₄;     -   R₁₀ represents hydrogen, C₁₋₆ alkyl or CO₂R₁₅;     -   R₁₁ represents hydrogen, C₁₋₆ alkyl, C₁₋₆ alkanoyl, halogen,         amino, C₁₋₆ acylamino, C₁₋₆ alkoxy, OH or CF_(3,); NHC₁₋₆ alkyl,         or N(C₁₋₆ alkyl)₂, where said alkyl may be substituted with 1-3         groups of halo, OH or C₁₋₆ alkoxy;     -   R₁₂ represents hydrogen, C₁₋₆ alkyl, NH2, C₁₋₆ alkylamino, C₁₋₆         alkoxy or C₁₋₆ dialkylamino, where said alkyl may be substituted         with 1-3 groups of halo, OH or C₁₋₆ alkoxy;     -   Each R₁₃ represents independently hydrogen, C₁₋₆ alkyl, NR₅R₆,         SR₈, S(O)R₈, S(O)2R₈, CN, C₁₋₆ alkylS(O)R, C₁₋₆ alkoxycarbonyl         hydroxycarbonyl, C₁₋₆acyl,     -   C₃₋₇ membered carbon ring optionally interrupted with 1-4         heteroatoms chosen from O, S, SO, SO₂, NH and NR8 where said         C₁₋₆ alkyl or C₁₋₆ acyl groups may be independently substituted         with 0-3 halogens, hydroxy, N(R)₂, CO₂R, C₆₋₁₀aryl,         C₅₋₁₀heteroaryl, or C₁₋₆alkoxy groups;     -   When two R₁₃ groups are attached to the same atom or two         adjacent atoms they may be taken together to form a 3-7 membered         ring optionally interrupted with 1-2 heteroatoms chosen from O,         S, SO, SO₂, NH, and NR₈;     -   R₁₄ represents amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, five to six         membered heterocycles or phenyl, said phenyl and heterocycles         optionally substituted with 1-3 group of halo, C₁₋₆ alkoxy, C₁₋₆         acylamino, or C₁₋₆ alkyl, hydroxy and/or amino, said amino and         hydroxy optionally protected with an amino or hydroxy protecting         group;     -   R₁₅ is C₁₋₆ alkyl or benzyl said benzyl optionally substituted         with 1-3 groups of halo, OH, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino,         or C₁₋₆ alkyl; and     -   m, n, and q represents 0-1.

Another aspect of the invention is concerned with the use of the novel antibiotic compositions in the treatment of bacterial infections.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms defined below unless otherwise specified.

The term “alkyl” refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight or branched. Preferred alkyl groups include lower alkyls which have from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and t-butyl. When substituted, alkyl groups may be substituted with up to 3 substituent groups, selected from the groups as herein defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with “branched alkyl group”.

Cycloalkyl is a species of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When substituted, cycloalkyl groups may be substituted with up to 3 substituents which are defined herein by the definition of alkyl.

Alkanoyl refers to a group derived from an aliphatic carboxylic acid of 2 to 4 carbon atoms. Examples are acetyl, propionyl, butyryl and the like.

The term “alkoxy” refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.

refers to aryl or heteroaryl, heterocycle, Het, heterocyclyl or heterocyclic as described immediately below.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused. e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.

The term heterocycle, heteroaryl, Het, heterocyclyl or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized (in which case it is properly balanced by a counterion), and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The heterocycle, heteroaryl, Het or heterocyclic may be substituted with 1-3 groups of R₇. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Additional examples of heteroaryls are illustrated by formulas a, b, c and d:

wherein R₁₆ and R₁₇ are independently selected from hydrogen, halogen, C₁₋₆ alkyl, C₂₋₄ alkanoyl, C₁₋₆ alkoxy; and R₁₈ represents hydrogen, C₁₋₆ alkyl, C₂₋₄ alkanoyl, C₁₋₆ alkoxycarbonyl and carbamoyl.

The term “alkenyl” refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.

The terms “quaternary nitrogen” and “positive charge” refer to tetravalent, positively charged nitrogen atoms (balanced as needed by a counterion known in the art) including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e.g. tetramethylammonium), heteroarylium, (e.g., N-methyl-pyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.

The term “heteroatom” means O, S or N, selected on an independent basis.

The term “prodrug” refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process. Exemplary prodrugs include acyl amides of the amino compounds of this inventon such as amides of alkanoic(C₁₋₆)acids, amides of aryl acids (e.g., benzoic acid) and alkane(C₁₋₆)dioic acids.

Halogen and “halo” refer to bromine, chlorine, fluorine and iodine.

When a group is termed “substituted”, unless otherwise indicated, this means that the group contains from 1 to 3 substituents thereon.

When a functional group is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene. T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.

Examples of suitable hydroxyl and amino protecting groups are: trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like. Examples of suitable carboxyl protecting groups are benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, t-butyl and the like.

The bicyclo[3.1.0]hexane containing oxazolidinone compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects. The term “pharmaceutically acceptable ester, salt or hydrate,” refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist. i.e. those which are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel bicyclic[3.1.0]hexane containing oxazolidinone compounds.

The pharmaceutically acceptable salts referred to above also include acid addition salts. Thus, the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

The pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include those which are hydrolyzed under physiological conditions, such as “biolabile esters”, pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others.

Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degrada-tion and other factors. Examples of biolabile esters include compounds.

An embodiment of this invention is realized when A is CH and all other variables are as described herein.

An embodiment of this invention is realized when A is C and --- is present.

Another embodiment of this invention is realized when A is N and all other variables are as described herein.

Another embodiment of this invention is realized When R₁ and R₂ independently represent H NR₅R₆, CN, OH, C(R)₂OR₁₄, NHC(═X1)N(R₁₃)₂, C(═NOH)N(R₁₃)₂, or CR₇R₈R₉ and all other variables are as described herein.

Another embodiment of this invention is realized when

-   -   is phenyl, pyridine, pyrimidine, or piperidine and all other         variables are as described herein.

Another embodiment of this invention is realized when one of R₁ and R₂ is H and the other is NR₅R₆ and all other variables are as described herein.

Another embodiment of this invention is realized when one of R₁ and R₂ is H and the other is CN and all other variables are as described herein.

Still another embodiment of this invention is realized when R₅ and R₆ independently are:

-   -   i) H,     -   ii) C₁₋₆ alkyl optionally substituted with 1-3 groups of         halogen, CN, OH, C₁₋₆ alkoxy, amino, hydroxyamino, alkoxyamino,         C₁₋₆ acyloxy, C₁₋₆ alkylsulfenyl, C₁₋₆ alkylsulfinyl, C₁₋₆         alkylsulfonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, C₁₋₆         dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine,         5-isoxazolyl, ethyenyloxy, or ethynyl, said phenyl and pyridine         optionally substituted with 1-3 halogen, CN, OH, CF₃, C₁₋₆ alkyl         or C₁₋₆ alkoxy;     -   iii) C₁₋₆ acyl optionally substituted with 1-3 groups of         halogen, OH, SH, C₁₋₆ alkoxy, naphthalenoxy, phenoxy, amino,         C₁₋₆ acylamino, hydroxylamino, alkoxylamino, C₁₋₆ acyloxy,         phenyl, pyridine, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylamino, C₁₋₆         dialkylamino, C₁₋₆ hydroxyacyloxy, C₁₋₆ alkylsulfenyl,         phthalimido, maleimido, succinimido, said phenoxy, phenyl and         pyridine optionally substituted with 1-3 groups of halo, OH, CN,         C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl; or     -   iv) benzoyl optionally substituted with 1-3 groups of halogen,         OH, C₁₋₆ alkoxy, C₁₋₆ alkyl, CF3, C₁₋₆ alkanoyl, amino or C₁₋₆         acylamino and all other variables are as described herein.

Yet another embodiment of this invention is realized when X₁ represents O and all other variables are as described herein.

Another embodiment of this invention is realized when one of R₁ or R₂ is hydrogen and the other is:

wherein R₁₀, X₁, m, q, and R₁₁ are described herein.

A preferred embodiment of this invention is realized when the structural formula is II:

-   -   wherein R₁, R₂, R₃, R₄, R_(4a), and Rx are as described herein         and A is N.

An embodiment of this invention is realized when A is C and --- is present.

Another preferred embodiment of this invention is realized when the structural formula is IIIa, or IIIb:

wherein R₁, R₂, R₃, R₄, R_(4a), and Rx are as described herein and A is N.

An embodiment of this invention is realized when A is C and --- is present.

Preferred compounds of this invention are:

-   N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyloxyacetyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(N-hydroxyacetyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyloxyacetyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(N-hydroxyacetyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(3-isoxazolyl)oxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Acetylamino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Benzoylamino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-phenylsulfonylamino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methanesulfonylamino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-carbamoylamino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Carboxyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-Iminoethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Bromomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[4-[1-(5(S)-Acetylaminomethyl-2-oxooxazolidin-3-yl)-3-fluoro]phenyl-(1α,5α,6α)-3-azabicyclo[3.1.0]hexan-6-yl]methylpyridinium     bromide. -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-succinimidoyloxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Carbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methoxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[N′,N″-Bis(benzyloxycarbonyl)guanigino]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-guanidino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methylcarbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Dimethylcarbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(piperidin-1-yl)carbonyl]-3-azabicyclo[3.1]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(morpholin-4-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   [5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[N-(2-hydroxyethyl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(2-Aminoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(1-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Acetyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   (E)-N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   (Z)-N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(methoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-Butoxycarbonylmethyloxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(Carboxylmethyloxyimino)methyl]-3-azabicyclo[31.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[((5S)-3-{4-[(1R,5R,6S)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Aminobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide     hydrochloride. -   N-[((5S)-3-{4-[(1S,5S,6R)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide, -   N-[5(S)-3-[4-[(1R,5R,6S)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1S,5S,6R)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1R,5R,6S)-6-Aminobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1S,5S,6R)-6-Aminobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1R,5R,6S)-6-Aminobicyclo[3.1.0]hex-2-en-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1S,5S,6R)-6-Aminobicyclo[3.1.0]hex-2-en-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1R,5R,6S)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1S,5S,6R)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1R,5R,6S)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1S,5S,6R)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,4α,5α,6α)-6-Aminobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,4β,5α,6α)-6-Aminobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,4α,5α,6α)-6-Aminobicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,4β,5α,6α)-6-Aminobicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,4α,5α,6α)-6-Cyanobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,4β,5α,6α)-6-Cyanobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,4α,5α,6α)-6-Cyanobicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,4β,5α,6α)-6-Cyanobicyclo[3.1.0]hexan-3-yl]-3.5     difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,4α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,4β,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,4α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,4β,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   (E)-N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)aminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   (Z)-N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)aminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-(methoxy)ethoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(Dimethylamino)ethoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(3-(Dimethylamino)propoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(N-(4-morpholinyl)imino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(1-t-Butoxycarboxyl-1-methyl)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(1-Carboxyl-1-methyl)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-hydroxyethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(5-tetrazolylmethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide     N-Oxide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Ethenyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(t-Butyldimethylsilyl)oxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(2-hydroxyethyl)-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(1,2-Dihydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(2-(t-Buthyldimethylsilyl)oxy-1-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(t-Buthyldimethylsilyl)oxy)acetyl]-3-azabicyclo[3.1.0]hexan-3-yl]3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxyacetyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(2,3-Dihydroxy)propyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(1,3-Dihydroxy)propyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(1-(2-(2-hydroxyethoxy))ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(Cyanomethyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylthio)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylsulfinyl)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylsulfonyl)     ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin     ylmethyl]acetamide. -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Aminomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(hydroxyethyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(2-Aminoethyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5     ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(pyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-Cyanopyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-Cyanopyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-Cyanopyrazin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(pyrimidin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-(4-Aminopyrimidin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5     difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(1-(2,3-dihydroxy)propyloxy)     iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(2-(1,3-dihydroxy)propyloxy)     iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(1-(2-(2-hydroxyethoxy)ethoxy)     iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(2-hydroxyethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, -   N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide. -   5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-(methoxythiocarbonyl)aminomethyloxazolidin-2-one, -   5(R)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-(isoxazol-3-yl)oxymethyloxazolidin-2-one, -   5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-(isoxazol-3-yl)aminomethyloxazolidin-2-one, -   5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-(isoxazol-3-yl)aminomethyloxazolidin-2-one, -   5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-(1,2,4-oxadiazol-3-yl)aminomethyloxazolidin-2-one, -   5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-(1,2,4-oxadiazol-3-yl)aminomethyloxazolidin-2-one,     and -   5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-(pyridin-2-yl)aminomethyloxazolidin-2-one.

Alternatively, compounds of the claimed invention are represented as Example Number Structure 1

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The following are also preferred compounds of the invention: 5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one, 5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[(isoxazolyl-3-yl)amino]methyl oxazolidin-2-one, 5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one, 5(S)-3-[4-[(1α,5α,6α)-6-Cyano bicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)]aminomethyl oxazolidin-2-one, 5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one, 5(R)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one, N-[5(S)-3-[4-[(1α,5α,6α)-6-[(N-Cyano-1-iminoethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-Amino-4-cyano-1,3-oxazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-Amino-4-cyano-1,3-oxazol-2-yl)bicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[4-[(1α,5α,6α)-6-Hydroxy methylbicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-[(Hydroxyamino)methyl]bicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano bicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6β)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[4-[(1α,5α,6β)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[4-[(1α,5α,6β)-6-Hydroxy methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6β)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-Hydroxymethylbicyclo [3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer A), N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer A), N-[5(S)-3-[4-[(1α,5α,6α)-6-Hydroxymethyl bicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer B), N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer B), N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-Cyano-2-dimethylamino)ethen-1-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-Amino-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, (E)-N-[5(S)-3-[4-[(1α,5α,6α)-6-[Amino (hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, (Z)-N-[5(S)-3-[4-[(1α,5α,6α)-6-[Amino (hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-[1-(2-t-Butyldiphenylsilyloxy-1-hydroxy)ethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(t-Butyldiphenylsilyl)oxy)acetyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[5-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[5-[(1α,5α,6α)-[(t-Butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[5-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]bicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1R,5R,6S)-(6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[4-[(1S,5S,6R)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. N-[5(S)-3-[4-[(1α,5α,6α)-6-(1-Cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-(1-Cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, 5(S)-3-[4-[(1R,5R,6S)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one, 5(S)-3-[4-[(1S,5S,6R)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one, N-[5(S)-3-[6-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[6-[(1α,5α,6α)-6-(Hydroxyimino)methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[6-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide, N-[5(S)-3-[6-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]thioacetamide N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide. N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide, N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-thiocarbamoylbicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide, 5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin, 5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one, 5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(isoxazolyl-3-yl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazoldin-2-one, 5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one, 5(R)-3-[4-[(1α,5α,6α)-6-(t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one, 5(S)-3-[4-[(1R,5R,6S)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one, 5(S)-3-[4-[(1S,5S,6R)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one.

Suitable subjects for the administration of the formulation of the present invention include mammals, primates, man, and other animals. In vitro antibacterial activity is predictive of in vivo activity when the compositions are administered to a mammal infected with a susceptible bacterial organism.

Using standard susceptibility tests, the compositions of the invention are determined to be active against MRSA and enterococcal infections.

The compounds of the invention are formulated in pharmaceutical compositions by combining the compounds with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below.

The compounds may be employed in powder or crystalline form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically, orally and parenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may be prepared in unit dosage form in ampules, or in multidose containers. The injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents. Alternatively, the active ingredient may be in powder (lyophilized or non-lyophilized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water. In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.

Topical applications nay be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.

Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions. The oral compositions may utilize carriers such as conventional formulating agents, and may include sustained release properties as well as rapid delivery forms.

The dosage to be administered depends to a large extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters, however, are left to the routine discretion of the physician according to principles of treatment well known in the antibacterial arts. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the compound.

The novel antibiotic compositions of this invention for human delivery per unit dosage, whether liquid or solid, comprise from about 0.01% to as high as about 99% of the bicyclo[3.1.0]hexane discussed herein, the preferred range being from about 10-60% and from about 1% to about 99.99% of one or more of other antibiotics such as those discussed herein, preferably from about 40% to about 90%. The composition will generally contain from about 125 mg to about 3.0 g of the bicyclo[3.1.0]hexane discussed herein; however, in general, it is preferable to employ dosage amounts in the range of from about 250 mg to 1000 mg and from about 200 mg to about 5 g of the other antibiotics discussed herein; preferably from about 250 mg to about 1000 mg. In parenteral administration, the unit dosage will typically include the pure compound in sterile water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and isotonic.

The invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal the claimed composition in an amount effective to treat said infection.

The preferred methods of administration of the claimed compositions include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection formulated so that a unit dosage comprises a therapeutically effective amount of each active component or some submultiple thereof.

For adults, about 5-50 mg/kg of body weight, preferably about 250 mg to about 1000 mg per person of the bicyclo[3.1.0]hexane antibacterial compound and about 250 mg, to about 1000 mg per person of the other antibiotic(s) given one to four times daily is preferred. More specifically, for mild infections a dose of about 250 mg two or three times daily of the bicyclo[3.1.0]hexane antibacterial compound and about 250 mg two or three times daily of the other antibiotic is recommended. For moderate infections against highly susceptible gram positive organisms a dose of about 500 mg each of the bicyclo[3.1.0]hexane and the other antibiotics, three or four times daily is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of about 500-2000 mg each of the bicyclo[3.1.0]hexane and the other antibiotics, three to four times daily may be recommended.

For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg is typically recommended.

The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The following examples further illustrate details for the preparation of compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare the compounds of the present invention. All temperatures are in degrees Celsius unless otherwise noted.

The compounds of the present invention are prepared according to the Schemes I-VI. In the Schemes that follow N is used to denote an appropriate leaving group and as such may vary in nature depending on the exact reaction conditions employed. Some typical leaving groups may be fluoro, chloro, bromo, iodo, tosyl, mesyl, trifluoromethanesulfonate etc. but these should not be construed as limiting as many leaving groups are well known to those skilled in the art. Scheme I describes the preparation of compounds of the invention in which A is a nitrogen atom and the 3-azabicyclo[3.1.0]hexane has a 6 amino substituent. In step 1 of scheme I a 6-amino-3-azabicyclo[3.1.0]hexane in which the 6-amino substituent is appropriately protected with the protecting groups P and P′ is allowed to react with an aryl or appropriate heteroaryl compound bearing a nitro Group and a leaving group in the presence or absence of a solvent. Appropriate protecting groups are well known to those skilled in the art and may include but are not limited to such groups as t-butoxycarbonyl, benzyloxycarbonyl or easily removed alkyl substituents such as the benzyl substituent. Examples of appropriate aryl and heteroaryl reaction partners may include, but are not limited to, 3,4-difluoro-nitrobenzene, 4-fluoronitrobenzene, or 2-nitro-5-fluoropyridine. Examples of appropriate solvents that may be employed are acetonitrile, tetrahydrofuran, methylene chloride, dichloroethane, toluene, dichlorobenzene, or other such solvents well known to those skilled in the art. The reaction is allowed to proceed at an appropriate temperature, which, depending on the solvent may be between 0° C. and 150° C. until such time that the reaction is determined to be complete. The product is then isolated and may or may not be further purified at the pleasure of the investigator and carried on to step 2.

The nitroaryl or heteroaryl compound obtained in step 1 is reduced to the corresponding amino compound in step 2. This transformation may be accomplished by a variety of reducing agents familiar to those skilled in the art such as hydrogenation over an appropriate catalyst such as palladium, platinum, or ruthenium on activated carbon or by chemical methods such reaction FeCl₃, SnCl₂, or ZnCl₂. The resulting amine is then protected with an appropriate protecting group. P″, such as benzyloxycarbonyl or t-butoxycarbonyl. The resulting protected aryl or heteroaryl amines are then isolated and earned on to step 3.

In step 3 the protected aryl or heteroaryl amine obtained as the product of step 2 is further reacted with a strong base such as n-butyl lithium or t-butyl lithium to form an anionic species which is then condensed with a glycidyl ester to form the 5-hydroxymethyloxazolidinone which is the product of step 3. It should be realized that reaction with a racemic glycidyl ester will result in the preparation of a racemic 5-hydroxymethyloxazolidinone while reaction with a chiral glycidyl ester will result in a chiral oxazolidinone. If an R-glycidylester is employed the product will be an R-5-hydroxymethyloxazolidinone and likewise if an S-glycidylester is employed the product will be an S-5-hydroxymethyloxazolidinone. Step 3 is conducted in a suitable solvent such as ether or tetrahydrofuran and is generally conducted at a temperature between −100° C. and 50° C. for a time necessary for complete reaction to occur. In a preferred embodiment of this reaction a solution of n-butyl lithium is added to a solution of the aryl or heteroaryl amine at −78° C. then the glycidyl ester is added and the resulting mixture allowed to warm to room temperature until the reaction is judged to be complete. The product is then isolated from the reaction mixture by standard techniques and, if necessary, the product may be purified.

In step 4 of Scheme I, the 5-hydroxymethyloxazolidinone is converted to a 5-aminomethyloxazolidinone in a three step process. First the hydroxy group is activated by conversion to a leaving group, X. This is generally accomplished by acylation with acylating agents such as methanesulfonyl chloride, p-toluenesulfonyl chloride or the like, generally with the addition of a hindered base such as triethylamine, diisoproproylethyl amine or the like to scavenge the acid produced in the reaction. Alternatively, if the nature of X is chosen to be a halide such as a bromide or iodide then reagents such as phosphorous tribromide, triphenylphosphonium dibromide or triphenylphosphonium diiodide may be chosen. Suitable solvents include but are not limited to ether, acetonitrile, tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride or dichloroethane, pyridine, collidine, or dioxane. In a second step the leaving group is displaced with sodium azide in a suitable solvent such as dimethylformamide, dimethylsulfoxide, or tetramethylurea, tetrahydrofuran and the like at a temperature between 0° C. and 100° C. When the reaction is judged to be complete the product is isolated and the resulting 5-azidooxazolidinone is reduced to the amine. A number of methods for the reduction of azides to amines may be used including hydrogenation over an appropriate catalyst such as palladium or platinum, particularly deactivated catalysts such as Lindlar's catalyst (palladium on CaCO₃ deactivated with PbO), or other reducing agents may be employed such as triphenylphosphine or SnCl₂. The particular method chosen for this reduction is readily made by one of ordinary skill in the art and is dependent upon the structure of the entirety of the molecule.

In step 5 the 5-aminooxazolidinone is acylated and converted to R₃. It is recognized that the exact nature of the reagents used for this conversion is dependent is dependent on the exact nature of the R₃ desired. For example if R₃ is desired to be an acetylamine group a suitable reagents for performing the acylation would be acetic anhydride, acetyl chloride or the like. However if R₃ is desired to be a thioacetylamine group ethyldithioacetate may be an appropriate acylating agent, while 1,1′-thiocarbonyldi-2(1H)-pyridone followed by treatment of the resulting intermediate with aqueous ammonia might be an appropriate procedure if thioureido group was desired for R₃. The appropriate conditions and reagents for any particular R₃ group will be readily identified by those of ordinary skill in the art.

Further elaboration of the compounds of the present invention prepared in Scheme I may be carried out by the methods shown in Scheme II. In this case in step 1-4 the amino protecting groups, P and P′ may be removed together or sequentially by procedures which will be familiar to those skilled in the art for the particular P and P′ to be removed. In certain cases a protecting group P may also be present in the compound of the present invention. For example in the case where P is benzyl and P′ is t-butoxycarbonyl simple removal of P′ by treatment with an appropriate acid such as trifluoroacetic acid or hydrochloric acid in a suitable solvent such as methanol of methylene chloride will result in a compound in which P′ is removed and P is retained. As shown in step 5 in some cases the compound in which P is retained may be further modified by means of reductive alkylation, alkylation or acylation to form compounds. Which are also of the present invention and incorporate an R₅ as described in the specification. Those skilled in the art will recognize that there are a variety of reagents and reaction conditions available for performing this chemical transformation which include, but are not limited to, the treatment of the product of step 2 with aldehydes, such as formaldehyde, and a reducing agent such as sodium cyanoborohydride, treatment with acylating agents such as anhydrides, acid chlorides, isocyanates, iminoethers, isothiouronium salts, sulfonyl halides, or treatment Faith alkylating agents such as alkyl iodides, bromides, triflates, or mesylates. Some specific examples of detailed reagents and reaction conditions for carrying out step 5 are detailed in the examples but these should not be construed as limiting for the preparation of compounds of current invention.

In a similar manner step 6 exemplifies the further modification compounds in which both of the protecting group, P and P′, have been removed. Those skilled in the art will recognize that there are a variety of reagents and reaction conditions available for performing, this chemical transformation which include, but are not limited to, the treatment of the completely deprotected product of step 3 or 4 with aldehydes, such as formaldehyde, and a reducing agent such as sodium cyanoborohydride, treatment with acylating agents such as anhydrides, acid chlorides, isocyanates, iminoethers, isothiouronium salts, sulfonyl halides, or treatment with alkylating agents such as alkyl iodides, bromides, triflates, or mesylates. Some specific examples of detailed reagents and reaction conditions for carrying out step 6 are detailed in the examples but these should not be construed as limiting for the preparation of compounds of current invention.

As can be seen for step 7, the product of step 5 may be further modified by removal of the protecting group P to afford the same products as those obtained by step 6. It is recognized that the exact conditions for the removal of P will depend on the exact nature of P but these procedures are well known and can be easily determined by those of ordinary skill in the art.

Step 8 exemplifies the procedures employed for the incorporation of R₆, which is structurally independent from that of R₅. As shown in step 8, the product of step 6 or 7 may be further modified by alkylation or acylation. Those skilled in the art will recognize that there are a variety of reagents and reaction conditions available for performing this chemical transformation which include, but are not limited to, the treatment of the product of step 6 or 7 with aldehydes, such as formaldehyde, and a reducing agent such as sodium cyanoborohydride, treatment with acylating agents such as anhydrides, acid chlorides, isocyanates, iminoethers, isothiouronium salts, sulfonyl halides, or treatment with alkylating agents such as alkyl iodides, bromides, triflates, or mesylates. Some specific examples of detailed reagents and reaction conditions for carrying out step 8 are detailed in the examples but these should not be construed as limiting for the preparation of compounds of current invention.

Scheme III describes the preparation of compounds of the invention in which A is a nitrogen atom and the 3-azabicyclo[3.1.0]hexane has a 6 carbon substituent. The synthetic sequence is similar to that described in Scheme I except that P′″ is a protecting group suitable for the protection of an hydroxyl group or is an alkyl group. Examples of appropriate P′″ include, but are not limited to alkyl groups, such as methyl, aralkyl groups such as benzyl or p-methoxybenzyl, silyl groups such as t-butyldiphenylsilyl, t-butyldimethylsilyl and the like, or ether groups such as tetrahydropyranyl or methoxymethyl. In step I of scheme III a 3-azabicyclo[3.1.0]hexane in which the 6-alkyl substituent is appropriately protected with the protecting groups P′″ is allowed to react with an aryl or appropriate heteroaryl compound bearing a nitro group and a leaving group in the presence or absence of a solvent. Examples of appropriate aryl and heteroaryl reaction partners may include, but are not limited to, 3,4-difluoro-nitrobenzene, 4-fluoronitrobenzene, or 2-nitro-5-fluoropyridine. Examples of appropriate solvents that may be employed are acetonitrile, tetrahydrofuran, methylene chloride, dichloroethane, toluene, dichlorobenzene, or other such solvents well known to those skilled in the art. The reaction is allowed to proceed at an appropriate temperature, which, depending on the solvent may be between 0° C. and 150° C. until such time that the reaction is determined to be complete. The product is then isolated and may or may not be further purified at the pleasure of the investigator and carried on to step 2.

The nitroaryl or heteroaryl compound obtained in step 1 is reduced to the corresponding amino compound in step 2. This transformation may be accomplished by a variety of reducing agents familiar to those skilled in the art such as hydrogenation over an appropriate catalyst such as palladium, platinum, or ruthenium on activated carbon or by chemical methods such reaction FeCl₃, SnCl₂, or ZnCl₂. The resulting amine is then protected with an appropriate protecting group, P″, such as benzyloxycarbonyl or t-butoxycarbonyl. The resulting protected aryl or heteroaryl amines are then isolated and carried on to step 3.

In step 3 the protected aryl or heteroaryl amine obtained as the product of step 2 is further reacted with a strong base such as n-butyl lithium or t-butyl lithium to form an anionic species which is then condensed with a glycidyl ester to form the 5-hydroxymethyloxazolidinone which is the product of step 3. It should be realized that reaction with a racemic glycidyl ester will result in the preparation of a racemic 5-hydroxymethyloxazolidinone while reaction with a chiral glycidyl ester will result in a chiral oxazolidinone. If an R-glycidylester is employed, the product will be an S-5-hydroxymethyloxazolidinone and likewise if an S-glycidylester is employed the product will be an R-5-hydroxymethyloxazolidinone. Step 3 is conducted in a suitable solvent such as ether or tetrahydrofuran and is generally conducted at a temperature between −100° C. and 50° C. for a time necessary for complete reaction to occur. In a preferred embodiment of this reaction a solution of n-butyl lithium is added to a solution of the aryl or heteroaryl amine at −78° C., then the glycidyl ester is added and the resulting mixture allowed to warm to room temperature until the reaction is judged to be complete. The product is then isolated from the reaction mixture by standard techniques and, if necessary, the product may be purified.

In step 4 of Scheme I, the 5-hydroxymethyloxazolidinone is converted to a 5-aminomethyloxazolidinone in a three step process. First the hydroxy group is activated by conversion to a leaving group, X. This is generally accomplished by acylation with acylating agents such as methanesulfonyl chloride, p-toluenesulfonyl chloride or the like, generally with the addition of a hindered base such as triethylamine, diisoproproylethyl amine or the like to scavenge the acid produced in the reaction. Suitable solvents include but are not limited to ether, tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride or dichloroethane, pyridine, collidine, or dioxane. In a second step the leaving group is displaced with sodium azide in a suitable solvent such as dimethylformamide, dimethylsulfoxide, tetramethylurea, or tetrahydrofuran and the like at a temperature between 0° C. and 100° C. When the reaction is judged to be complete the product is isolated and the resulting 5-azidooxazolidinone is reduced to the amine. A number of methods for the reduction of azides to amines may be used including hydrogenation over an appropriate catalyst such as palladium or platinum, particularly deactivated catalysts such as Lindlar's catalyst (palladium on CaCO₃ deactivated with PbO), or other reducing agents may be employed such as triphenylphosphine or SnCl₂. The particular method chosen for this reduction is readily made by one of ordinary skill in the art as is dependent upon the structure of the entirety of the molecule.

In step 5 the 5-aminooxazolidinone is acylated and converted to R₃. It is recognized that the exact nature of the reagents used for this conversion is dependent is dependent on the exact nature of the R₃ desired. For example if R₃ is desired to be an acetylamine group a suitable reagents for performing the acylation would be acetic anhydride, acetyl chloride or the like. However if R₃ is desired to be a thioacetylamine group ethyldithioacetate may be an appropriate acylating agent, while 1,1′-thiocarbonyldi-2(1H)-pyridone followed by treatment of the resulting intermediate with aqueous ammonia might be an appropriate procedure if thioureido group was desired for R₃. The appropriate conditions and reagents for any particular R₃ group will be readily identified by those of ordinary skill in the art.

Scheme IV describes the further modification of compound prepared in Scheme III. It is recognized that in many cases the product of step 5 from Scheme III is in and of itself a compound of the current invention. This may particularly be true when P′″ is an alkyl or aralkyl group. However, in other cases further chemical modification of the product of step 5 from Scheme III may be desirable. A general method for these chemical modifications is exemplified in Scheme IV. In step 1 the protecting group P′″ is removed to reveal the free hydroxymethyl group for further manipulation. It is recognized that the precise reaction conditions for step 1 will be dependent on the structure of the molecule in its entirety in general and on the particular structural nature of the precise P′″ to be removed. Such reaction conditions are readily determined by those of ordinary skill in the art. Step 2 exemplifies the direct activation and displacement of the hydroxy group by substituents with a hydroxy group. This transformation is typically performed by the in situ activation of the hydroxy towards displacement with an azodicarboxylate ester such as diethyl azodicrboxylate or diisopropylazodicarboxylate, in the presence of a phosphine such as triphenylphosphine in an aprotic solvent such as tetrahydrofuran. However a more general way of activating the hydroxyl towards displacement with a wide variety of potential nucleophiles is exemplified in step 3 and involves the modification of the hydroxy group to a leaving group, X. It will be recognized by those skilled in the art that the particular conditions and reagents employed will be dependent on the particular group X. This is generally accomplished by acylation with acylating agents such as methanesulfonyl chloride, p-toluenesulfonyl chloride or the like, generally with the addition of a hindered base such as triethylamine, diisoproproylethyl amine or the like to scavenge the acid produced in the reaction. Alternatively, if a the nature of X is chosen to be a halide such as a bromide or iodide then reagents such as phosphorous tribromide, triphenylphosphonium dibromide, carbon tetrabromide and triphenyl phoshine, or triphenylphosphonium diiodide may be chosen. Suitable solvents include but are not limited to ether, acetonitrile, tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride or dichloroethane, pyridine, collidine, or dioxane.

Step 4 exemplifies the procedure for the conversion of the product of step 3 to compounds of the instant invention containing an R₇ substituent. It is to be recognized that the leaving groups as defined by X above form a subset of the substructures represented in R₇ and as such are incorporated into the current invention. It is the further modification of these intermediates that is described in step 4. The reaction conditions required for the introduction of R₇ will vary depending on the exact nature of the R₇ employed as will be readily recognized by one of ordinary skill in the art but generally involve the reaction of a nucleophile in the appropriate solvent with the product of step 3 containing a leaving group X at a temperature between −78° C. and 150° C. sufficient for the reaction to proceed at the desired rate. When the reaction is judged to be complete the product of step 4 is isolated using conditions well known to those skilled in the art. Some representative nucleophiles that may be used to further exemplify, but not limit, step 4 include carbon nucleophiles, such as cyanide, enolate anions, or organometallic anions, nitrogen nucleophiles, such amines, imide anions, and nitrogen containing heteroaryl compounds, oxygen nuclophiles, such as alkoxides or hydroperoxides, or sulfur nucleophiles such as thiolates.

In step 5 of Scheme 4, the hydroxymethyl compound is oxidized to the corresponding aldehyde. A plethora of reagents is available to those skilled in the art for performing this transformation. Among these are chromium based reagents such as chromium trioxide and complexes of chromium trioxide with pyridine in solvents such as pyridine of methylene chloride, cerium ammonium nitrate, N-chlorosuccininmide, dimethylsulfoxide and activating agents such as oxalyl chloride or dicyclohexylcarbodiimide, and 1-hydroxy-1,2-benziodoxol-2(1H)-one 1-oxide in dimethylsulfoxide.

In step 6 the aldehyde prepared in step 5 is further oxidized to the acid under conditions well known to those skilled in the art. A preferred reagent for performing this transformation is silver oxide although a variety oxidizing agents such as peracids, including m-chloroperbenzoic acid, peracetic acid and trifluoroperacetic acid, chromic acid, or bromine may be considered as non-limiting alternatives.

In step 7 the carboxylic acid produced as the product of step 6 can be further modified. Typically this is may be done by converting the hydroxyl of the carboxylic acid to a leaving group. Although it is readily recognized that many potential leaving groups can be considered and are well known to those of only ordinary skill in the art, some preferred methods include conversion of the carboxylic acid to the acid chloride by treatment with thionyl chloride or oxalyl chloride, formation of a mixed anhydride by treatment with a dehydrating agent such dicyclohexylcarbodiimide followed by a 2,2-dimethylpropionic acid, or formation of an active ester by treatment with a dehydrating agent such as dicyclohexylcarbodiimide and N-hydroxysuccinimide or pentfluorophenol. The resulting activated carboxylic acid may then be treated with a nucleophile, either in situ or after intermediate isolation of the activated carboxylic acid, to produce the molecules of the instant invention. Typical solvents for this transformation are well known and include methylene chloride, chloroform, carbon tetrachloride, ethers such as tetrahydrofuran, dioxane, and diethyl ether, ethyl acetate and other esters. Typical nucleophiles include alcohols to form esters, primary or secondary amines or ammonia to form amides, and carbon nucleophiles such as organometallic species to afford ketones and tertiary carbinol derivatives.

The preparation of the compounds of the present invention where A contains a carbon atom is shown in Schemes V-VI. In step 1 of Scheme V an appropriately protected 3-trifluoromethansulfonyl-6-amino-bicyclo[3.1.0]hexene is reacted with a suitably substituted 2-oxo-3-(4-trimethylstannylphenyl)-5-substituted oxazolidinone in the presence of an appropriate solvent and a palladium catalyst to afford the cross-coupled product. A preferred amino protecting group is bis (t-butoxycarbonyl). Preferred palladium catalysts include but are not limited to tris(dibenzylideneacetone)palladium, and mixtures of palladium on carbon, copper(I)iodide and triphenylarsenate and the like. A preferred solvent is N-methylpyrollidinone. Upon isolation the product of step 2 may be further modified in a fashion directly analogous to those described in Scheme II. Alternatively in step 2 of Scheme V the double bond may be reduced by hydrogenation in the presence of a catalyst to afford the corresponding bicyclo[3.1.0]hexane. It is recognized that the particular conditions employed for this hydrogenation may differ depending on the exact compound desired but generally hydrogen pressures between 1-100 atmospheres will be applied at a temperature between 0° C. and 10° C. An appropriate catalyst will be readily chosen by those skilled in the art, but may include palladium, ruthenium, or platinum on carbon. In turn the bicyclo[3.1.0]hexane obtained may be further modified by methods analogous to those described in Scheme II.

Scheme VI describes the preparation of further compounds of the present invention in which A contains a carbon atom. In step 1 of Scheme VI an appropriately protected 3-trifluoromethansulfonyl-6-hydroxymethyl-bicyclo[3.1.0]hexene is reacted with a suitably substituted 2-oxo-3-(4-trimethylstannylphenyl)-5-substituted oxazolidinone in the presence of an appropriate solvent and a palladium catalyst to afford the cross-coupled product. A preferred hydroxy protecting group is the t-butyldiphenylsilyl group. Preferred palladium catalysts include but are not limited to tris(dibenzylideneacetone)palladium, and mixtures of palladium on carbon, copper(I)iodide and triphenylarsenate and the like. A preferred solvent is N-methylpyrollidinone. Upon isolation the product of step my be further modified in a fashion directly analogous to those described in Scheme IV. Alternatively in step 2 of Scheme VI the double bond may be reduced by hydrogenation in the presence of a catalyst to afford the corresponding bicyclo[3.1.0]hexane. It is recognized that the particular conditions employed for this hydrogenation may differ depending on the exact compound desired but generally hydrogen pressures between 1-100 atmospheres will be applied at a temperature between 0° C. and 100° C. An appropriate catalyst will be readily chosen by those skilled in the art, but may include palladium, ruthenium, or platinum on carbon. In turn the bicyclo[3.1.0]hexane obtained may be further modified by methods analogous to those described in Scheme IV.

Antibacterial Activity

The pharmaceutically-acceptable compounds of the present invention are useful antibacterial agents having a rood spectrum of activity in vitro against standard bacterial strains, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically-acceptable compounds of the present invention show activity against vancomycin-resistant enterococci, streptococci including penicillin-resistant S. pneumoniae, methicillin-resistant S. aureus, M. catarrhalis, and C. pneumoniae. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.

The following in vitro results were obtained based on an agar dilution method except for C. pneumoniae. The activity is presented as the minimum inhibitory concentration (MIC).

S. aureus and M. catarrhalis were tested on Mueller-Hinton agar, using an approximate inoculum of 1×10⁴ cfu/spot an incubation temperature of 35C for 24 hours. The MIC was defined as the lowest concentration at which no visible bacterial growth was observed.

Streptococci and enterococci were tested on Mueller-Hinton agar supplemented with 5% defibrinated horse blood, using an approximate inoculum of 1×10⁴ cfu/spot an incubation temperature of 35° C. in an atmosphere of 5% CO₂ for 24 hours. The MIC was defined as the lowest concentration at which no visible bacterial growth was observed.

C. pneumoniae was tested using minimum essential medium supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 1 mg/ml cycloheximide and non essential amino acid. HeLa 229 cells were inoculated with 104 inclusion-forming units of C. pneumoniae strain per mL. Infected cells were incubated with test compounds in complete medium at 35C in an atmosphere of 5% CO₂ for 72 hours. Cells monolayers were fixed in methanol, stained for chlamydial inclusions with an fluorescein-conjugated anti-Chlamydia monoclonal antibody, and were observed with fluorescence microscope. The MIC was defined as the lowest concentration at which no inclusion was observed. MIC (μg/ml) Strains Example 8 Example 22 Example 41 Example 46 Linezolid Staphylococcus aureus Smith 0.5 0.06 0.06 0.25 1 CR 4 0.5 0.5 1 16 MR 1 0.016 0.06 0.25 1 Streptococcus pneumontae IID553 1 0.5 0.5 0.5 2 PRQR 1 0.5 0.5 0.25 1 Streptococcus pyogenes IID692 0.5 0.5 0.5 0.25 1 Enterococcus faecium VRQR 2 0.5 0.5 0.5 2 Moraxella catarrhalis ATCC25238 NT 2 4 2 4 Chlamydia pneumoniae ATCC VR-1360 0.5 NT NT NT 8 CR = chloramphenicol resistant MR = methicillin resistant PRQR = penicillin resistant, quinolone resistant VRQR = vancomycin resistant, quinolone resistant NT = not tested

The invention described herein is exemplified by the following non-limiting examples. The compound data is designated in accordance to General Guidelines for Manuscript Preparation, J. Org. Chem. Vol. 66, pg. 19A, Issue 1, 2001.

EXAMPLE 1 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxy carbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (3.02 g) in methanol (9 mL) was added a solution of hydrogen chloride in methanol (6 mL) at 0° C., and the mixture was stirred at room temperature for 3 hours. After diluting the mixture by the addition of dichloromethane, the solution was made to alkaline by the addition of saturated sodium hydrogencarbonate solution. The resulting mixture was extracted with dichloromethane. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, dichloromethane:methanol=8:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6 (N-benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (2.32 g).

¹H NMR (CDCl₃) δ 1.66 (s, 2H), 2.02 (s, 3H), 2.23 (t, J=2.0 Hz, 1H), 3.25 (d, J=8.8 Hz, 2H), 3.50-3.80 (m, 5H), 3.84 (s, 2H), 3.98 (t, J=8.8 Hz, 1H), 4.70-4.80 (m, 1H), 6.56 (t, J=9.3 Hz, 1H), 6.97 (dd, J=9.3, 2.0 Hz, 1H), 7.20-7.40 (m, 6H).

MS (EI⁺) m/z: 438 (M⁺).

HRMS (EI⁺) for C₂₄H₂₇FN₄O₃ (M⁺): calcd, 438.2067; found, 438.2066.

EXAMPLE 2 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyloxyacetyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (716 mg) and triethylamine (861 μL) in dichloromethane (4 mL) was added benzyloxyacetyl chloride (512 μL) at 0° C., and the mixture was stirred at the same temperature for 30 min. After quenching the reaction by the addition of 1N hydrochloric acid, the mixture was extracted with dichloromethane. The dichloromethane solution was washed with water, aqueous hydrogencarbonate solution and brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=10:1) of the residue gave N-[5(S)-3-[4-(1α,5α,6α)-6-(N-benzyloxyacetyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (673 mg).

¹H NMR (CDCl₃) δ 1.78 (s, 2H), 2.02 (s, 3H), 2.76 (d, J=2.4 Hz, 1H), 3.27 (d, J=8.8 Hz, 2H), 3.50-3.80 (m, 5H), 3.90-4.10 (m, 1H), 3.97 (s, 2H), 4.56 (s, 2H), 4.70-4.80 (m, 1H), 6.59 (t, J=9.3 Hz, 1H), 6.98 (dd, J=9.3, 2.4 Hz, H), 7.20-7.40 (m, 6H).

MS (EI⁺) m/z: 496 (M⁺).

HRMS (EI⁺) for C₂₆H₂₉FN₄O₅ (M⁺): calcd, 496.2122; found, 496.2152.

EXAMPLE 3 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(N-hydroxyacetyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyloxyacetyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (476 mg) and palladium catalyst (7.5% on charcoal, 476 mg) in methanol (24 mL) was added ammonium formate (445 mg), and the mixture was heated at reflux for 5 hours. After filtration of the catalyst, the filtrate was concentrated in vacuo to give N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(N-hydroxyacetyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (82.5 mg).

¹H NMR (DMSO-d₆) δ 1.82 (s, 3H), 1.87 (s, 2H), 2.60-2.70 (m, 1H), 3.19 (d, J=8.8 Hz, 2H), 3.6-3.39 (m, 2H), 3.60-3.70 (m, 3H), 3.78 (d, J=5.4 Hz, 2H), 4.03 (t, J=9.0 Hz, 1H), 4.60-4.70 (m, 1H), 6.77 (t, J=9.3 Hz, 1H), 7.08 (dd, J=9.3, 2.4 Hz, 1H), 7.38 (dd, J=16.1, 2.4 Hz, 1H).

MS (FAB⁺) m/z: 407 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₄FN₄O₅ (MH⁺): calcd, 407.1731; found, 407.1728.

EXAMPLE 4 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (954 mg) in tetrahydrofuran (14 mL) were added formalin (37%, 1.72 mL), sodium tris(acetoxy)borohydride (971 mg), and acetic acid (250 μL), and the mixture was stirred at room temperature for 2 hours. After quenching the reaction by the addition of aqueous sodium hydrogencarbonate solution, the resulting precipitates were collected by filtration, and then dissolved with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, dichloromethane:methanol=10:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (1.11 g).

¹H-NMR (CDCl₃) δ 1.64 (s, 2H), 1.79 (s, 1H), 2.02 (s, 3H), 2.30 (s, 3H), 3.23 (d, J=9.3 Hz, 2H), 3.50-3.80 (m, 7H), 3.99 (t, J=8.8 Hz, 1H), 4.70-4.80 (m, 1H), 6.57 (t, J=9.3 Hz, 1H), 6.98 (dd, J=9.3, 2.4 Hz, 1H), 7.20-7.40 (m, 6H).

MS (EI⁺) m/z: 452 (M⁺).

HRMS (EI⁺) for C₂₅H₂₉FN₄O₃ (M⁺): calcd, 452.2224; found, 452.2226.

EXAMPLE 5 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

A suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (794 mg) and palladium catalyst (7.5% on charcoal, 714 mg) in methanol (32 mL) was hydrogenated at 1 atm for 5.5 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo. Treatment of the residue with methanol gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (182 mg).

¹H NMR (DMSO-d₆) δ 1.66 (s, 2H), 1.76 (s, 1H), 1.82 (s, 3H), 2.27 (s, 3H), 3.19 (d, J=7.8 Hz, 2H), 3.30-3.40 (m, 2H), 3.55 (d, 2H), 3.64 (dd, J=8.8, 6.4 Hz, 1H), 4.02 (t, J=8.8 Hz, 1H), 4.60-4.70 (m, 1H), 6.70 (t, J=9.3 Hz, 1H), 7.05 (dd, J=9.3, 2.4 Hz, 1H), 7.35 (dd, J=16.1, 2.4 Hz, 1H).

MS (FAB⁺) m/z: 363 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₄FN₄O₃ (MH⁺): calcd, 363.1832; found, 363.1833.

EXAMPLE 6 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyloxyacetyl-N-methyl)amino-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyloxyacetyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (363 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (526 mg) in the same manner as described for EXAMPLE 2.

¹H NMR (CDCl₃) δ 1.91 (s, 2H), 2.02 (s, 3H), 2.72 (s, 1H), 2.96 (s, 3H), 3.26 (d, J=9.3 Hz, 2H), 3.50-3.80 (m, 5H), 3.99 (t, J=9.3 Hz, 1H), 4.32 (s, 2H), 4.68 (s, 2H), 4.70-4.80 (m, 1H), 6.58 (t, J=9.3 Hz, 1H), 6.90-7.10 (m, 1H), 7.20-7.40 (m, 6H).

MS (FAB⁺) m/z: 511 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₂FN₄O₅ (MH⁺): calcd, 511.2357; found, 511.2342.

EXAMPLE 7 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(N-hydroxyacetyl-N-methylamino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(N-hydroxyacetyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (191 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyloxyacetyl-N-methyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (312 mg) in the same manner as described for EXAMPLE 3.

¹H NMR (DMSO-d₆) δ 1.82 (s, 3H), 2.09 (s, 2H), 2.65 (s, 1H), 2.84 (s, 3H), 3.24 (d, J=8.8 Hz, 2H), 3.36-3.39 (m, 2H), 3.60-3.70 (m, 3H), 4.03 (t, J=9.0 Hz, 1H), 4.24 (s, 2H), 4.60-4.70 (m, 1H), 6.76 (t, J=9.8 Hz, 1H), 7.08 (dd, J=9.8, 2.4 Hz, 1H), 7.38 (dd, J=16.1, 2.4 Hz, 1H).

MS (FAB⁺) m/z: 421 (MH⁺).

HRMS (FAB⁺) for C₂₀H₂₆FN₄O₅ (MH⁺): calcd, 421.1887; found, 421.1862.

EXAMPLE 8 N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoro phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

A suspension of 4-[(1α,5α,6α)-6-(N-benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cetamide (954 mg) and palladium catalyst (7.5% on charcoal, 668 mg) in methanol (38 mL) was hydrogenated at 1 atm for 7 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (716 mg).

¹H NMR (DMSO-d₆) δ 1.47 (s, 2H), 1.82 (s, 3H), 2.15 (s, 1H), 3.17 (d, J=8.8 Hz, 2H), 3.30-3.40 (m, 2H), 3.52 (dd, J=8.8, 2.4 Hz, 2H), 3.64 (dd, J=9.3, 6.4 Hz, 1H), 4.02 (t, J=9.3 Hz, 1H), 4.60-4.70 (m, 1H), 6.67-6.72 (m, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 7.35 (dd, J=16.1, 2.4 Hz, 1H).

MS (EI⁺) m/z: 348 (M⁺).

HRMS (EI⁺) for C₁₇H₂₁FN₄O₃ (M⁺): calcd, 348.1598; found, 348.1635.

EXAMPLE 9 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Step 1.

5(R)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one.

To a solution of 4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-benzyloxycarbonylamino-3-fluorobenzene (6.46 g) in dry tetrahydrofuran (65 mL) was added a solution of n-butyllithium in hexane (1.6 M, 8.51 mL) at −78° C., and the mixture was stirred at the same temperature for 30 min. (R)-Glycidyl butylate (2.11 mL) was added to the mixture at −78° C. and the mixture was allowed to stand at room temperature for 4 hours. After quenching the reaction with the addition of aqueous ammonium chloride solution and dilution with ethyl acetate, the resulting mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:5) of the residue gave 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (3.95 g).

¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.90 (s, 2H), 2.47 (s, 1H), 3.27 (d, J=8.8 Hz, 2H), 3.50-4.00 (m, 4H), 3.88 (dd, J=8.8, 6.8 Hz, 1H), 3.95 (t, J=8.8 Hz, 1H), 4.45 (s, 2H), 4.60-4.80 (m, 1H), 6.55 (t, J=9.3 Hz, 1H), 7.02 (dd, J=8.8, 2.4 Hz, 1H), 7.20-7.40 (m, 6H).

MS (EI⁺) m/z: 497 (M⁺).

Step 2.

5(R)-Azidomethyl-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one.

To a solution of 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxy carbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyl oxazolidin-2-one (3.95 g) in dichloromethane (119 mL) were successively added triethylamine (2.22 mL) and methanesulfonyl chloride (922 μL) at 0° C., and the mixture was stirred at the same temperature for 5 min. The mixture was washed with 1N hydrochloric acid, water, aqueous sodium hydrogencarbonate solution, and brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-methane sulfonyloxmethyloxazolidin-2-one. This was used in the next step without further purification. The mixture of crude 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-methane sulfonyloxymethyloxazolidin-2-one thus obtained and sodium azide (1.78 g) in N,N-dimethylformamide (90 mL) was heated at 70° C. for 15 hours, and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with water and brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=10:9) of the residue gave 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxy carbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (3.40 g).

¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.90 (s, 2H), 2.46 (s, 1H), 3.28 (d, J=8.8 Hz, 2H), 3.50-3.80 (m, 4H), 3.76 (dd, J=8.8, 6.1 Hz, 1H), 4.00 (t, J=8.8 Hz, 1H), 4.45 (s, 2H), 4.70-4.80 (m, 1H), 6.55 (t, J=9.3 Hz, 1H), 6.90-7.10 (m, 1H), 7.20-7.40 (m, 6H).

MS (EI⁺) m/z: 522 (M⁺).

Step 3.

5(R)-Aminomethyl-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one.

A suspension of 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (3.40 g) and Lindlar catalyst (5% palladium on CaCO3 partially poisoned with lead, 1.70 g) in dichloromethane (20 mL) and methanol (102 mL) was hydrogenated at 1 atm for 2.5 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give 5(R)-aminomethyl-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (3.27 g).

Step 4.

N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of 5(R)-aminomethyl-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (3.27 g) in dichloromethane (65 mL) was added triethylamine (1.09 mL) and acetic anhydride (696 μL) at 0° C., and the mixture was stirred at the same temperature for 30 min. After quenching the reaction by the addition of water, the mixture was extracted with dichloromethane. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate methanol=20:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (3.19 g).

¹H NMR (CDCl₃) δ 1.49 (s, 9H) 1.90 (s, 2H) 2.01 (s, 3H) 2.46 (s, 1H) 3.27 (d, J=8.3 Hz, 2H) 3.50-3.80 (m, 5H) 3.97 (t, J=9.0 Hz, 1H) 4.45 (s, 2H) 4.70-4.80 (m, 1H) 6.54 (t, J=9.3 Hz, 1H) 6.96 (dd, J=9.3, 2.4 Hz, 1H) 7.20-7.40 (m, 6H).

MS (EI⁺) m/z: 538 (M⁺).

EXAMPLE 10 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benz 1-N-t-butoxycarbonyl)amino-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide.

To a solution of 5(R)-aminomethyl-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (323 mg) in tetrahydrofuran (2 mL) was added triethylamine (200 μL) and ethyl dithioacetate (84 μL), and the mixture was stirred at room temperature for 11 days, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=4:5) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide (241 mg).

¹H NMR (CDCl₃) δ 1.58 (s, 9H), 1.80-2.00 (m, 2H), 2.40-2.50 (m, 1H), 2.59 (s, 3H), 3.28 (d, J=8.8 Hz, 2H), 3.60-3.70 (m, 2H), 3.75 (d, J=9.3, 6.8 Hz, 1H), 3.90-4.10 (m, 2H), 4.20-4.30 (m, 1H), 4.45 (s, 2H), 4.90-5.00 (m, 1H), 6.54 (t, J=9.3 Hz, 1H), 6.95 (dd, J=9.3, 2.4 Hz, 1H), 7.20-7.40 (m, 6H).

MS (FAB⁺) m/z: 555 (MH⁺).

EXAMPLE 11 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxy carbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide (238 mg) in methanol (2 mL) was added a solution of hydrogen chloride in methanol (4.4 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. After quenching the reaction by the addition of aqueous sodium hydrogencarbonate solution, the resulting mixture was extracted with dichloromethane. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=15:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide (114 mg).

¹H NMR (DMSO-d₆) δ 1.58 (s, 2H), 1.99 (s, 1H), 2.42 (s, 3H), 3.16 (d, J=9.3 Hz, 2H), 3.49 (dd, J=9.3, 2.9 Hz, 2H), 3.70 (s, 2H), 3.70-3.80 (m, 1H), 3.80-3.90 (m, 1H), 4.06 (t, J=9.0 Hz, 1H), 4.80-4.90 (m, 1H), 6.68 (t, J=8.8 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 7.20-7.40 (m, 6H).

MS (FAB⁺) m/z: 455 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₇FN₄O₂S (MH⁺): calcd, 454.1839; found, 455.1936.

EXAMPLE 12 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea

Step 1,

N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]isothiocyanate.

To a solution of 5(R)-aminomethyl-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (149 mg) in dichloromethane (3 mL) was added a solution of 1,1′-thiocarbonyldi-2(1H)-pyridone (86.2 mg) in dichloromethane (5 mL) at 0° C., and the mixture was stirred at room temperature for 3 hours. The mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=3:5) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]isothiocyanate (135 mg).

¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.90 (s, 2H), 2.45 (s, 1H), 3.29 (d, J=8.3 Hz, 2H), 3.50-3.80 (m, 2H), 3.70-4.00 (m, 3H), 4.10 (t, J=9.0 Hz, 1H), 4.45 (s, 2H), 4.70-4.80 (m, 1H), 6.56 (t, J=9.3 Hz, 1H), 7.01 (dd, J=9.3, 2.9 Hz, 1H), 7.20-7.30 (m, 6H).

MS (EI⁺) m/z: 538 (M⁺).

Step 2.

N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea

To a suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxy carbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]isothiocyanate (135 mg) in methanol (0.5 mL) was added a solution of ammonia in methanol (7N solution, 3.57 mL), and the mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo to give N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea. This compound was used without further purification. N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea (84.3 mg) was prepared from the crude N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea in the same manner as described for EXAMPLE 11.

¹H NMR (DMSO-d₆) δ 1.61 (s, 2H), 2.04 (s, 1H), 3.16 (d, J=9.3 Hz, 2H), 3.49 (dd, J=9.3, 2.0 Hz, 2H), 3.60-3.90 (m, 3H), 3.74 (s, 2H), 4.03 (t, J=9.0 Hz, 1H), 4.78 (brs, 1H), 6.69 (t, J=8.8 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 7.10-7.40 (m, 6H).

MS (FAB⁺) m/z: 456 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₇FN₅O₂S (MH⁺): calcd, 456.1870; found, 456.1850.

EXAMPLE 13 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl) oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (583 mg) in methanol (10 mL) was added a solution of hydrogen chloride in methanol (saturated, 1.5 mL), and the mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue was dissolved in water (5 mL), made to alkaline by the addition of saturated sodium hydrogencarbonate solution. The resulting precipitates were collected by filtration, washed with water, and then dried in vacuo to give N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (377 mg).

¹H NMR (DMSO-d6) δ 0.99-1.04 (m, 1H), 1.48-1.53 (m, 2H), 1.82 (s, 3H), 3.16 (d, J=8.9 Hz, 2H), 3.28-3.32 (m, 2H), 3.38 (t, J=5.4 Hz, 2H), 3.56 (dd, J=9.3, 2.0 Hz, 2H), 3.65 (dd, J=9.2, 6.4 Hz, 1H), 4.03 (t, J=9.3 Hz, 1H), 4.49 (t, J=5.4 Hz, 1H), 4.63-4.70 (m, 1H), 6.74 (t, J=9.3 Hz, 1H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 7.36 (dd, J=16.1, 2.4 Hz, 1H), 8.22 (t, J=5.4 Hz, 1H).

MS (EI⁺) m/z: 363 (M⁺)

EXAMPLE 14 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Step 1.

5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one.

The title compound 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (702 mg) was prepared from 1-benzyloxycarbonyl amino-3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (1.19 g) in the same manner as described for EXAMPLE 9.

MS (EI⁺) m/z: 406 (M⁺).

HRMS (EI⁺) for C₂₁H₂₇FN₂O₅ (M⁺): calcd, 406.1904; found, 406.1930.

Step 2.

5(R)-Azidomethyl-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one.

The title compound 5(R)-azidomethyl-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one (659 mg) was prepared from 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (698 mg) in the same manner as described for EXAMPLE 9.

MS (EI⁺) m/z: 431 (M⁺).

HRMS (EI⁺) for C₂₁H₂₆FN₅O₄(M⁺): calcd, 431.1969; found, 431.1960.

Step 3.

N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl) oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (588 mg) was prepared from 5(R)-azidomethyl-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one (655 mg) in the same manner as described for EXAMPLE 9.

EXAMPLE 15 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one

The title compound 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (345 mg) was prepared from 1-benzyloxycarbonylamino-3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (450 mg) in the same manner as described for EXAMPLE 9.

MS (EI⁺) m/z: 336 (M⁺).

HRMS (EI⁺) for C₁₇H₂₁FN₂O₄ (M⁺): calcd, 336.1485; found, 336.1477.

Step 2.

5(R)-Azidomethyl-3-[3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one.

The title compound 5(R)-azidomethyl-3-[3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one (332 mg) was prepared from 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxy methyloxazolidin-2-one (290 mg) in the same manner as described for EXAMPLE 9.

Step 3.

N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (286 mg) was prepared from 5(R)-azidomethyl-3-[3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one (332 mg) in the same manner as described for EXAMPLE 9.

MS (EI⁺) m/z: 377 (M⁺).

EXAMPLE 16 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(3-isoxazolyl)oxymethyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a suspension of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (500 mg), 3-hydroxyisoxazole (152 mg), and triphenylphosphine (541 mg) in tetrahydrofuran (6 mL) was added diisopropyl azodicarboxylate (362 mg), and the mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=9:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(3-isoxazolyl)oxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (398 mg).

MS (EI⁺) m/z: 430 (M⁺).

HRMS (EI⁺) for C₂₁H₂₃FN₄O₅(M⁺): calcd, 430.1652; found, 430.1698.

EXAMPLE 17 N-[5(S)-3-[4-[(1α,5α,6α)-6-Acetylamino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (105 mg) in pyridine (3 mL) was added acetic anhydride (57 μL), and the mixture was stirred at 50° C. for 2 hours, and then concentrated in vacuo. Flash chromatography (silica, dichloromethane:methanol=10:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-acetylamino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (88.6 mg).

MS (EI⁺) m/z: 390 (M⁺).

HRMS (EI⁺) for C₁₉H₂₃FN₄O₄(M⁺): calcd, 390.1703; found, 390.1694.

EXAMPLE 18 N-[5(S)-3-[4-[(1α,5α,6α)-6-Benzoylamino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (105 mg) in pyridine (1 mL) and dichloromethane (4 mL) was added benzoyl chloride (70 μL), and the mixture was stirred at 0° C. for 30 min, and then concentrated in vacuo. Flash chromatography (silica, dichloromethane:methanol=9:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-benzoylamino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (96.2 mg).

MS (EI⁺) m/z: 452 (M⁺).

HRMS (EI⁺) for C₂₄H₂₅FN₄O₄ (M⁺): calcd, 452.1860; found, 452.1874.

EXAMPLE 19 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-phenylsulfonylamino-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-phenylsulfonyl amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (97.7 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (105 mg) and benzenesulfonyl chloride (77 μL) in the same manner as described for EXAMPLE 18.

MS (EI⁺) m/z: 488 (M⁺).

HRMS (EI⁺) for C₂₃H₂₅FN₄O₅S (M⁺): calcd, 488.1530; found, 488.1547.

EXAMPLE 20 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methanesulfonylamino-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-mathane sulfonylamino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (118 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (105 mg) and methanesulfonyl chloride (46 μL) in the same manner as described for EXAMPLE 18.

MS (EI⁺) m/z: 426 (M⁺).

HRMS (EI⁺) for C₁₈H₂₃FN₄O₅S (M⁺): calcd, 426.1373; found, 426.1376.

EXAMPLE 21 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-carbamoylamino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (139 mg) in dimethylformamide (5 mL) was added trimethylsilyl isocyanate (0.27 mL), and the mixture was stirred at room temperature for 4 hours, and then concentrated in vacuo. Flash chromatography (silica, dichloromethane:methanol:NH₄OH=50:8:0.5) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-carbamoylamino-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (112 mg).

MS (EI⁺) m/z: 392 (M⁺).

HRMS (EI⁺) for C₁₈H₂₃FN₅O₄(M⁺): calcd, 392.1734; found, 392.1731.

EXAMPLE 22 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan 3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (1.00 g) in dimethyl sulfoxide (10 mL) was added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (1.16 g), and the mixture was stirred at room temperature for 2 hours. After dilution with water, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=19:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (766 mg).

MS (EI⁺) m/z: 361 (M⁺).

HRMS (EI⁺) for C₁₈H₂₀FN₃O₄(M⁺): calcd, 361.1438; found, 361.1469.

EXAMPLE 23 N-[5(S)-3-[4-[(1α,5α,6α)-6-Carboxyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (321 mg) in methanol (17 mL) were added 1N sodium hydroxide solution (1.78 mL) and silver(I) oxide (309 mg), and the mixture was stirred at room temperature for 6 hours. After insoluble materials were filtered off, the filtrate was concentrated in vacuo, and then the residue was added chloroform. The resulting precipitates were collected by filtration, washed with 1N hydrochloric acid and water, and then dried to give N-[5(S)-3-[4-[(1α,5α,6α)-6-carboxyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (297 mg).

MS (EI⁺) m/z: 377 (M⁺)

HRMS (EI⁺) for C₁₈H₂₀FN₃O₅(M⁺): calcd, 377.1387; found, 377.1367.

EXAMPLE 24 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-Iminoethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (139 mg) in methanol (5 mL) was added potassium carbonate (112 mg) and ethanimidic acid ethyl ester hydrochloride (98.8 mg), and the mixture was stirred at room temperature for 12 hours. After insoluble materials were filtered off, the filtrate was concentrated in vacuo. Flash chromatography (silica, dichloromethane:methanol:NH₄OH=20:10:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-iminoethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (76.9 mg).

MS (FAB⁺) m/z: 390 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₅FN₅O₃(MH⁺): calcd, 390.1941; found, 390.1966.

EXAMPLE 25 N-[5(S)-3-[4-[(1α,5α,6α)-6-Bromomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (36.3 mg) and tetrabromomethane (49.7 mg) in dichloromethane (1 mL) was added triphenylphosphine (39.3 mg), and the mixture was stirred at room temperature for 2 hours, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=19:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-bromomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (30.1 mg).

MS (EI⁺) m/z: 425 (M⁺).

HRMS (EI⁺) for C₁₈H₂₁BrFN₃O₃ (M⁺): calcd, 425.0750; found, 425.0739.

EXAMPLE 26 N-[5(S)-[4-[(1α,5α,6α)-6-Cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

A solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-bromomethyl-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (300 mg) and sodium cyanide (52.0 mg) in dimethylformamide (1.4 mL) was stirred at room temperature for 1 day, and then concentrated in vacuo. The residue was dissolved in dichloromethane, the solution was washed with water, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=19:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (259 mg).

MS (EI⁺) m/z: 372 (M⁺).

HRMS (EI⁺) for C₁₉H₂₁FN₄O₃ (M⁺): calcd, 372.1598; found, 372.1596.

EXAMPLE 27 N-[4-[1-(5(S)-Acetylaminomethyl-2-oxooxazolidin-3-yl)-3-fluoro]phenyl-(1α,5α,6α)-3-azabicyclo[3.1.0]hexan-6-yl]methyl pyridinium bromide.

A solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-bromomethyl-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (115 mg) in pyridine (5 mL) was stirred at room temperature for 3 days, and then concentrated in vacuo. The methanol solution of the residue was treated with charcoal, filtered, and then concentrated in vacuo. The aqueous solution of the residue was lyophilized to give N-[4-[1-(5(S)-acetylaminomethyl-2-oxooxazolidin-3-yl)-3-fluoro]phenyl-(1α,5α,6α)-3-azabicyclo[3.1.0]hexan-6-yl]methylpyridinium bromide (128 mg).

MS (FAB⁺) m/z: 425 [(M-Br)^(+].)

HRMS (FAB⁺) for C₂₃H₂₆FN₄O₃ [(M-Br)⁺]: calcd, 425.1989; found, 425.1950.

EXAMPLE 28 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-succinimidoyloxycarbonyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-carboxyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (280 mg) in dimethylformamide (5 mL) were added N-hydroxysuccinimide (124 mg) and 1,3-dicyclohexylcarbodiimide (230 mg), and the mixture as stirred at room temperature for 2 days. After insoluble materials were filtered off and washed with ethyl acetate. The filtrate was washed with saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=19:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-succinimidoyloxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (349 mg).

MS (FAB⁺) m/z: 475 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₄FN₄O₇ (MH⁺): calcd, 475.1629; found, 475.1618.

EXAMPLE 29 N-[5(S)-3-[4-[(1α,5α,6α)-6-Carbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-succinimidoyl oxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (160 mg) in tetrahydrofuran (5 mL) was added aqueous ammonium hydroxide solution (28%, 1 mL), and the mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue was treated with water, the resulting precipitates were collected by filtration and washed with water and tetrahydrofuran to give N-[5(S)-3-[4-[(1α,5α,6α)-6-carbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (115 mg).

MS (EI⁺) m/z: 376 (M⁺).

HRMS (EI⁺) for C₁₈H₂₁FN₄O₄(M⁺): calcd, 376.1547; found, 376.1552.

EXAMPLE 30 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α) -6-methoxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-carboxyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (100 mg) in dimethylformamide (2 mL) was added methanol (17.0 mg) and 1,3-dicyclohexylcarbodiimide (109 mg), and the mixture was stirred at room temperature for 6 hours, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=19:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-methoxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (101 mg).

MS (EI⁺) m/z: 391 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂FN₃O₅ (M⁺): calcd, 391.1543; found, 391.1515.

EXAMPLE 31 N-[5(S)-3-[4-[(1α,5α,6α)-6-[N′,N″-Bis(benzyloxycarbonyl)guanidino]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (157 mg) and 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (161 mg) in N,N-dimethylformamide (3 mL) was added triethylamine (125 μL), and the mixture was stirred at room temperature for 1 day. After dilution with dichloromethane, the mixture was washed with water and brine, dried over dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=5:2) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[N′,N″-bis(benzyloxycarbonyl)guanigino]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (288 mg).

MS (FAB⁺) m/z: 659 (MH⁺).

EXAMPLE 32 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-guanidino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

A suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-[N′,N″-bis(benzyloxy carbonyl)guanidino]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (224 mg) and palladium catalyst (10% on charcoal, 67.2 mg) in methanol (S mL) and dichloromethane (5 mL) was hydrogenated at 1 atm for 7 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-guanidino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (127 mg).

MS (FAB⁺) m/z: 390 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₄FN₆O₃(MH⁺): calcd, 391.1894; found, 390.1888.

EXAMPLE 33 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methylcarbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-succinimidoyl oxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (180 mg) in tetrahydrofuran (10 mL) was added methylamine (30% ethanol solution, 0.40 mL) at room temperature, and the mixture was stirred for 30 min. The resulting precipitates were collected by filtration, washed with water and tetrahydrofuran to give N-[5(S)-3-[3-fluoro-4-[(1 (1α,5α,6α)-6-methylcarbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (141 mg).

MS (EI⁺) m/z: 390 (M⁺).

HRMS (EI⁺) for C₁₉H₂₃FN₄O₄(M⁺): calcd, 390.1703; found, 390.1710.

EXAMPLE 34 N-[5(S)-3-[4-[(1α,5α,6α)-6-Dimethylcarbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-succinimidoyl oxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (180 mg) in tetrahydrofuran (4 mL) was added a solution of dimethylamine hydrochloride (309 mg) and sodium hydrogencarbonate (637 mg) in water (1 mL), and the mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue was treated with water, the resulting precipitates were collected by filtration and washed with water and tetrahydrofuran to give N-[5(S)-3-[4-[(1α,5α,6α)-6-dimethylcarbamoyl-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (138 mg).

MS (EI⁺) m/z: 404 (M⁺).

HRMS (EI⁺) for C₂₀H₂₅FN₄O₄ (M⁺): calcd, 404.1860; found, 404.1864.

EXAMPLE 35 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(piperidin-1-yl)carbonyl]-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-succinimidoyl oxycarbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) in tetrahydrofuran (5 mL) was added piperidine (135 mg), and the mixture was stirred at room temperature for 2 hours, and then concentrated in vacuo. The residue was treated with water, the resulting precipitates were collected by filtration and washed with water to give N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(piperidin-1-yl)carbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (128 mg).

MS (EI⁺) m/z: 444 (M⁻).

HRMS (EI⁺) for C₂₃H₂₉FN₄O₄(M⁺): calcd, 444.2173; found, 444.2152.

EXAMPLE 36 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(morpholin-4-yl)carbonyl]-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(morpholin-4-yl) carbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (128 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-succinimidoyl oxycarbonyl-3-azabicyclo[3.1. O]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and morpholine (138 mg) in the same manner as described for EXAMPLE 35.

MS (EI⁺) m/z: 446 (M⁺).

HRMS (EI⁺) for C₂₂H₂₇FN₄O₅ (M⁺): calcd, 446.1965; found, 446.1984.

EXAMPLE 37 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[N-(2-hydroxyethyl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[N-(2-hydroxyethyl)]carbamoyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (130 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-succinimidoyloxy carbonyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (180 mg) and ethanolamine (116 mg) in the same manner as described for EXAMPLE 35.

MS (FAB⁺) m/z: 420 (M⁺).

HRMS (FAB⁺) for C₂₀H₂₅FN₄O₅ (M⁺): calcd, 420.1809; found, 420.1779.

EXAMPLE 38 N-[5(S)-3-[4-[(1α,5α,6α)-6-(2-Aminoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoro phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (262 mg) in methanol (7 mL) was added cobalt(II) chloride hexahydrate (335 mg) and sodium borohydride (266 mg) at 0° C., and the mixture was stirred for 1 hour. After quenching the reaction by the addition of 1N hydrochloric acid (7 mL), and the mixture was stirred at room temperature for 30 min, and then concentrated in vacuo. The residue was made to alkaline by the addition of ammonium hydroxide solution, and then concentrated in vacuo. Flash chromatography (silica NH type, ethyl acetate:methanol=9:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(2-aminoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (139 mg).

MS (FAB⁺) m/z: 376 (M⁺).

HRMS (FAB⁺) for C₁₉H₂₅FN₄O₃ (M⁺): calcd, 376.1911; found, 376.1899.

EXAMPLE 39 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(1-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (340 mg) in dioxane (20 mL) was added methylmagnesium iodide(3.0M solution in diethyl ether 1.25 mL) at 0° C., and the mixture was stirred at room temperature for 14 hours. After quenching the reaction by the addition of saturated ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=50:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(1-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (163 mg).

MS (EI⁺) m/z: 377 (M⁺).

HRMS (EI⁺) for C₁₉H₂₄FN₃O₄(M⁺): calcd, 377.1751; found, 377.1740.

EXAMPLE 40 N-[5(S)-3-[4-[(1α,5α,6α)-6-Acetyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(1-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (160 mg) in dimethyl sulfoxide (4 mL) was added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (178 mg), and the mixture was stirred at room temperature for 6 hours. After dilution the mixture with saturated sodium hydrogencarbonate solution, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=20:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-acetyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (19 mg).

MS (EI⁺) m/z: 375 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂FN₃O₄(M⁺): calcd, 375.1594; found, 375.1556.

EXAMPLE 41 (E)-N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (130 mg) and sodium acetate (177 mg) in methanol (5 mL) was added hydroxylamine hydrochloride (75.0 mg), and the mixture was stirred at room temperature for 2 hours, and then concentrated in vacuo. The residue was treated with water, and the resulting precipitates were collected by the filtration, washed with water to give (E)-N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (132 mg).

MS (EI⁺) m/z: 376 (M⁺).

HRMS(EI⁺) for C₁₈H₂₁FN₄O₄ (M⁺): calcd, 376.1547; found, 376.1558.

EXAMPLE 42 (Z)-N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (100 mg) and sodium acetate (90.8 mg) in methanol (5 mL) was added hydroxylamine hydrochloride (38.5 mg), and the mixture was stirred at room temperature for 20 min, and then concentrated in vacuo. The residue was treated with water, and the resulting precipitates were collected by the filtration, washed with water. The methanol solution of the filtrate was concentrated in vacuo. Preparative thin layer chromatography (silica, ethyl acetate:methanol=20:1) of the residue gave (Z)-N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (34.0 mg).

MS (EI⁺) m/z: 376 (M⁺).

HRMS (EI⁺) for C₁₈H₂₁FN₄O₄(M⁺): calcd, 376.1547; found, 376.1582.

EXAMPLE 43 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(methoxyimino)methyl]-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(methoxyimino) methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (152 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and O-methylhydroxylamine hydrochloride (104 mg) in the same manner as described for EXAMPLE 41.

MS (EI⁺) m/z: 390 (M⁺).

HRMS (EI⁺) for C₁₉H₂₃FN₄O₄(M⁺): calcd, 390.1703; found, 390.1717.

EXAMPLE 44 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-Butoxycarbonylmethyloxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of O-(t-butoxycarbonylmethyl)hydroxylamine (157 mg) in methanol (7 mL) was added N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (350 mg), and the mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate: methanol=20:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-butoxycarbonylmethyloxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (473 mg).

MS (EI⁺) m/z: 490 (M⁺).

HRMS (EI⁺) for C₂₄H₃₁FN₄O₆ (M⁺): calcd, 490.2228; found, 490.2273.

EXAMPLE 45 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(Carboxylmethyloxyimino)methyl]-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-butoxycarbonylmethyloxyimino) methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (220 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at 0° C., and the mixture was stirred at room temperature for 12 hours, and then concentrated in vacuo. The residue was treated with water and acetonitrile, and the resulting precipitates were collected by filtration to give N-[5(S)-3-[4-[(1α,5α,6α)-6-[(carboxylmethyloxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (120 mg).

MS (FAB⁺) m/z: 433 [(M−H)^(+].)

HRMS (FAB⁺) for C₂₀H₂₂FN₄O₆ [(M−H)⁺]: calcd, 433.1523; found, 433.1501.

EXAMPLE 46 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (164 mg) in tetrahydrofuran (3 mL) was added diisopropyl azodicarboxylate (151 mg) and triphenylphosphine (392 mg), and the mixture was stirred at room temperature for 10 min. Flash chromatography (silica, ethyl acetate:methanol=9:1) of the mixture gave N-[5(S)-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg).

MS (EI⁺) m/z: 358 (M⁺).

HRMS (EI⁺) for C₁₈H₁₉FN₄O₃ (M⁺): calcd, 358.1441; found, 358.1477.

EXAMPLE 47 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

A suspension of lithium chloride (25 mg), tris(dibenzylideneacetone) dipalladium(0)-chloroform adduct (10 mg), and (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-[(trifluoromethanesulfonyl)oxy]bicyclo[3.1.0]hex-2-ene (99 mg) in N-methylpyrrolidone (0.4 mL) was stirred at room temperature for 5 min under Ar atmosphere. The resulting mixture was added a solution of N-[5(S)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (100 mg) in N-methylpyrrolidone (0.4 mL), and the mixture was stirred at room temperature for 16 hours. After addition of ethyl acetate and water, insoluble materials were filtered off. The organic extracts were washed with 10% ammonium hydroxide solution, water, and brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=30:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (79 mg).

¹H NMR (CDCl₃) δ 0.73-0.75 (m, 1H), 1.05 (s, 9H), 1.50-1.60 (m, 1H), 1.80-1.90 (m, 1H), 2.02 (s, 3H), 2.60-2.70 (m, 1H), 2.90-3.00 (m, 1H), 3.50-3.80 (m, 5H), 4.04 (t, J=8.8 Hz, 1H), 4.76-4.78 (m, 1H), 6.47 (m, 1H), 7.10-7.70 (m, 13H).

MS (FAB⁺) m/z: 599 (MH⁺).

EXAMPLE 48 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl) oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (383 mg) in tetrahydrofuran (2 ml) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 1.28 mL) at 0° C., and the mixture was stirred at room temperature for 2.5 hours. After dilution the mixture with water, the resulting mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=10:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (111 mg).

¹H NMR (DMSO-d₆) δ 0.50-0.60 (m, 1H), 1.56-1.60 (m, 1H), 1.81 (s, 3H), 1.87-1.90 (m, 1H), 2.70 (d, J=17.1 Hz, 1H), 2.95 (dd, J=17.1, 7.3 Hz, 1H), 3.20-3.40 (m, 2H), 3.40 (t, J=5.4 Hz, 2H), 3.71 (dd, J=8.8, 6.4 Hz, 1H), 4.10 (t, J=8.8 Hz, 1H), 4.68-4.75 (m, 1H), 6.43 (m, 1H), 7.21-7.24 (m, 1H), 7.33 (t, J=8.8 Hz, 1H), 7.40-7.50 (m, 1H).

MS (FAB⁺) m/z: 361 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₂FN₂O₄ (MH⁺): calcd, 361.1564; found, 361.1555.

EXAMPLE 49 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a suspension of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl bicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (270 mg) in dichloromethane (8 mL) were added N-methylmorpholine N-oxide (136 mg), molecular sieves 4A (powdered, 188 mg), and tetrapropylammonium perruthenate (27 mg) at room temperature, the resulting mixture was stirred for 1 hour. After insoluble materials were filtered off, the filtrate was concentrated in vacuo to give N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. This was used in the next step without further purification. Sodium acetate (375 mg) was added a solution of hydroxylamine hydrochloride (165 mg) in methanol (8 mL), the mixture was stirred at room temperature for 1 hour. The resulting mixture was added crude N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide and methanol (5 mL), and the whole was sonicated for 10 minutes and stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue was diluted with water, the resulting precipitates were collected by filtration, and then dried in vacuo to give N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]bicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. This was used in the next step without further purification. To a suspension of crude N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(hydroxyimino) methyl]bicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide in tetrahydrofuran (8 mL) were added diisopropyl azodicarboxylate (228 mg) and triphenylphosphine (608 mg), and the mixture was stirred at room temperature for 2 hours, allowed to stand overnight, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=10:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (173 mg).

¹H NMR (CDCl₃) δ 0.90-1.00 (m, 1H), 2.02 (s, 3H), 2.30-2.40 (m, 1H), 2.68-2.72 (m, 1H), 2.90 (d, J=17.6 Hz, 1H), 3.18 (dd, J=17.6, 6.4 Hz, 1H), 3.60-3.80 (m, 2H), 3.77 (dd, J=8.8, 6.4 Hz, 1H), 4.04 (t, J=8.8 Hz, 1H), 4.76-4.82 (m, 1H), 6.45 (m, 1H), 7.14 (dt, J=8.3, 2.0 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H), 7.43 (dt, J=14.2, 2.0 Hz, 1H).

MS (EI⁺) m/z: 355 (M⁺).

HRMS (EI⁺) for C₁₉H₁₈FN₃O₃ (M⁺): calcd, 355.1332; found, 355.1354.

EXAMPLE 50 N-[5(S)-3-[4-[(1α,5α,6α)-6-Aminobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide Hydrochloride

A suspension of lithium chloride (286 mg), tris(dibenzyl ideneacetone) dipalladium(0)-chloroform adduct (233 mg), and (1α,5α,6α)-6-[bis(t-butoxycarbonyl) amino]-3-[(trifluoromethanesulfonyl)oxy]-bicyclo[3.1.0]hex-2-ene (997 mg) in N-methylpyrrolidone (6 mL) was stirred at room temperature for 5 min under Ar atmosphere. The resulting mixture was added a solution of N-[5(S)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (1.12 g) in N-methylpyrrolidone (6 mL), and the mixture was stirred at 40° C. for 24 hours. After dilution the mixture with ethyl acetate and water, insoluble materials were filtered off. The organic extracts were washed with 10% ammonium hydroxide solution, water, and brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate acetone=5:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[bis(t-butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (503 mg). To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-[bis(t-butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (503 mg) in tetrahydrofuran (1 mL) was added a solution of hydrogen chloride in ethanol (1 mL), and the mixture was stirred at room temperature for 1 hour. After dilution the mixture with diethyl ether, the resulting precipitates were collected by filtration to give N-[5(S)-3-[4-[(1α,5α,6α)-6-aminobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamidehydrochloride (161 mg).

mp: 215-220° C.

¹H NMR (DMSO-d₆) δ 1.81 (s, 3H), 2.00-2.03 (m, 1H), 2.03-2.10 (m, 1H), 2.40-2.42 (m, 1H), 2.81 (d, J=17.1 Hz, 1H), 3.06 (dd, J=17.1, 7.3 Hz, 1H), 3.30-3.70 (m, 2H), 3.72 (dd, J=8.8, 6.4 Hz, 1H), 4.10 (t, J=8.8 Hz, 1H), 4.70-4.80 (m, 1H), 6.34 (s, 1H), 7.20-7.30 (dt, 1H), 7.37 (t, J=8.8 Hz, 1H), 7.46-7.50 (dt, 1H).

MS (FAB⁺) m/z: 346 (MH⁺) (free base).

HRMS (FAB⁺) for C₁₈H₂₁FN₃O₃ (MH⁺): calcd, 346.1567; found, 346.1571 (free base).

EXAMPLE 51 N-[5(S)-3-[4-[(1α,5α,6α)-6-Azidomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

A suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-bromomethyl-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (213 mg) and sodium azide (114 mg) in DMF (3 mL) was heated at 70° C. for 48 hours. After diluting the mixture with ethyl acetate, the solution was washed water and brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=15:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-azidomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (160 mg).

MS (EI⁺) m/z: 388 (M⁺).

HRMS (EI⁺) for C₁₈H₂₁FN₆O₃ (M⁺): calcd, 388.1659; found, 388.1697.

EXAMPLE 52 N-[5(S)-3-[4-[(1α,5α,6α)-6-Aminomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

A uspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-azidomethyl-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (153 mg) and palladium catalyst (10% on charcoal, 31 mg) in methanol (5 mL) and dichloromethane (1 mL) was hydrogenated at 1 atm for 4.5 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo. Treatment of the residue with ethanol-diisopropyl ether gave N-[5(S)-3-[4-[(1α,5α,6α)-6-aminomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoro phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (132 mg).

MS (EI⁺) m/z: 362 (M⁺).

HRMS (EI⁺) for C₁₈H₂₃FN₄O₃ (M⁺): calcd, 362.1754; found, 362.1782.

EXAMPLE 53 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(pyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The mixture of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (348 mg), 2-pyridyl triflate (295 mg) and triethylamine (209 μL) in DMSO (2 mL) was heated at 100° C. for 36 hours. After diluting the mixture with dichloromethane-methanol (10:1), the mixture was washed with water, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=12:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(pyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (76.5 mg).

¹H NMR (DMSO-d₆) δ 1.76 (s, 2H), 1.82 (s, 3H), 3.27-3.40 (m, 5H), 3.64-3.74 (m, 3H), 4.04 (t, J=9.0 Hz, 1H), 4.67 (m, 1H), 6.53-6.57 (m, 2H), 6.74-6.80 (m, 2H), 7.09 (dd, J=8.8, 2.4 Hz, 1H), 7.37-7.47 (m, 2H), 7.99 (d, J=3.7 Hz, 1H), 8.27 (t, J=5.9 Hz, 1H).

MS (EI⁺) m/z: 425 (M⁺).

EXAMPLE 54 (E)-N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-Benzyl-(N-benzyloxycarbonyl)methyl]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl)amino-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (592 mg) and potassium carbonate (224 mg) in DMF (4.5 mL) was added benzyl bromoacetate (235 μL) at 0° C., and the mixture was stirred at room temperature for 2.5 hours. After diluting the mixture with ethyl acetate, the solution was washed water and brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=25:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-benzyl-(N-benzyloxycarbonyl)methyl]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (756 mg).

MS (EI⁺) m/z: 587 (M⁺).

HRMS (EI⁺) for C₃₃H₃₆FN₄O₅ (M⁺): calcd, 587.2670; found, 587.2669.

EXAMPLE 55 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Step 1.

N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[N-benzyl-N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

A suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-benzyl-(N-benzyloxycarbonyl) methyl]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (751 mg), lithium chloride (271 mg) and sodium borohydride (242 mg) in tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 12 hours. After diluting the mixture with water, the solution was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, dichloromethane methanol:acetone=15:1:0.5) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[N-benzyl-N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (601 mg).

Step 2.

N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

A suspension of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[N-benzyl-N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (594 mg) and palladium catalyst (10% on charcoal, 297 mg) in methanol (5 mL) was hydrogenated at 1 atm for 8 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (482 mg).

MS (FAB⁺) m/z: 393 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₆FN₄O₄(MH⁺): calcd, 393.1938; found, 393.1949.

EXAMPLE 56 N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-Benzyloxycarbonyl-N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To the mixture of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[N-(2-hydroxy ethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (287 mg) and sodium hydrogencarbonate (61.3 mg) in dioxane (4 mL) and water (1.6 mL) was added benzyl chloroformate (104 μL) at 0° C., and the mixture was stirred at the same temperature for 20 min. After diluting the mixture with ethyl acetate, the solution was washed water and brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-benzyloxycarbonyl-N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (228 mg).

MS (FAB⁺) m/z: 526 (M−H⁺).

HRMS (FAB⁺) for C₂₇H₃₁FN₄O₆ (MH⁺): calcd, 526.2228; found, 526.2203.

EXAMPLE 57 N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-(2-Azidoethyl)-N-benzyloxycarbonyl]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Step 1.

N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-Benzyloxycarbonyl-N-(2-methanesulfonyl oxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-benzyloxycarbonyl-N-(2-hydroxyethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (211 mg) in dichloromethane (4 mL) was added triethylamine (279 μL) and methanesulfonyl chloride (155 mL) at 0° C., and the mixture was stirred at the same temperature for 20 min. The mixture was washed with water, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-benzyloxycarbonyl-N-(2-methanesulfonyloxyethyl)]amino-3-azabicyclo[3.1.0]hexan -3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (276 mg).

Step 2.

N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-(2-Azidoethyl)-N-benzyloxycarbonyl]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. The mixture of N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-benzyloxycarbonyl-N-(2-methanesulfonyloxy ethyl)]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (276 mg) and sodium azide (91.0 mg) in DMF (3 mL) was heated at 70° C. for 12 hours. After diluting the mixture with ethyl acetate, the solution was washed water. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=20:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-(2-azidoethyl)-N-benzyloxy carbonyl]amino-3-azabicyclo[3.1.0.]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (158 mg).

MS (FAB⁺) m/z: 551 (M−H⁺).

HRMS (FAB⁺) for C₂₇H₃₀FN₇O₅ (M−H⁺): calcd, 551.2292; found, 551.2282.

EXAMPLE 5 N-[5(S)-3-[4-[(1α,5α,6α)-6-(2-Aminoethyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

A suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-[N-(2-azidoethyl)-N-benzyloxy carbonyl]amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (155 mg) and palladium catalyst (10% on charcoal, 77.5 mg) in tetrahydrofuran (4 mL) and ethanol (2 mL) was hydrogenated at 1 atm for 7 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo. Flash chromatography (NH-silica, dichloromethane:methanol=97:3) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(2-aminoethyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (65.3 mg).

MS (FAB⁺) m/z: 392 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₇FN₅O₃(MH⁺): calcd, 392.2098; found, 392.2107.

EXAMPLE 59 N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-Cyanopyrazin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

The mixture of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (105 mg), 3-chloro-2-cyanopyrazine (46.0 mg), and triethylamine (63 μL) was heated at 100° C. for 6 hours. Flash chromatography (silica, ethyl acetate:methanol=7:3) of the mixture gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-cyanopyrazin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (75.3 mg).

MS (EI⁺) m/z: 451 (M⁺).

HRMS (EI⁺) for C₁₉H₂₇FN₅O₃(M⁺): calcd, 451.1768; found, 451.1742.

EXAMPLE 60 N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-Cyanopyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-cyanopyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (100 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (105 mg), 2-chloro-3-cyanopyridine (46 mg) in the same manner as described for EXAMPLE 59.

MS (EI⁺) m/z: 450 (M⁺).

HRMS (EI⁺) for C₂₃H₂₃FN₆O₃ (M⁺): calcd, 450.1816; found, 450.1838.

EXAMPLE 61 N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-Cyanopyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-cyanopyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (135 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (139 mg), 2-chloro-5-cyanopyridine (67 mg) in the same manner as described for EXAMPLE 59.

MS (EI⁺) m/z: 450 (M⁺).

HRMS (EI⁺) for C₂₃H₂₃FN₆O₃ (M⁺): calcd, 450.1816; found, 450.1799.

EXAMPLE 62 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(pyrimidin-2-ylamino-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(pyrimidin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (109 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (105 mg), 2-fluoropyrimidine (44 mg) in the same manner as described for EXAMPLE 59.

MS (EI⁺) m/z: 426 (M⁺).

HRMS (EI⁺) for C₂₁H₂₃FN₆O₃ (M⁺): calcd, 426.1816; found, 426.1825.

EXAMPLE 63 N-[5(S)-3-[4-[(1α,5α,6α)-6-(t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan -3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]amine (126 mg) in pyridine (2 mL) was added difluoroacetic anhydride (81 mg) at 0° C., and the mixture was stirred at room temperature for 1 hour. After dilution of the mixture with ethyl acetate, the solution was washed with 1 N hydrochloric acid, brine and saturated sodium hydrogencarbonate solution. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, dichloromethane:acetone=5:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide (108 mg).

MS (EI⁺) m/z: 484 (M⁺).

HRMS (EI⁺) for C₂₂H₂₇F₃N₄O₅(M⁺): calcd, 484.1934; found, 484.1889.

EXAMPLE 64 N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide

To a suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide (169 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), the mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. After dilution the residue with dichloromethane and methanol, the mixture was added saturated sodium hydrogencarbonate solution, and then concentrated in vacuo. Flash chromatography (silica, dichloromethane:acetone=5:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide (95.3 mg).

MS (EI⁺) m/z: 384 (M⁺).

HRMS (EI⁺) for C₁₇H₁₉F₃N₄O₃ (M⁺): calcd, 384.1409; found, 406.1389.

EXAMPLE 65 (E)-N-[5(S)-3-[4-[(1α,5α,6α)-6-[Amino(hydroxyimino)methyl]-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide and (Z)-N-[5(S)-3-[4-[(1α,5α,6α)-6-[amino(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoro phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (180 mg) in ethanol was added hydroxylamine hydrochloride (210 mg) and sodium acetate (494 mg) was heated at reflux for 30 hours, and then concentrated in vacuo. After addition of water to the residue, the resulting precipitates were collected by filtration and dried in air. Flash chromatography (silica, dichloromethane:methanol=4:1) of the precipitates gave (E)-N-[5(S)-3-[4-[(1α,5α,6α)-6-[amino(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxo oxazolidin-5-ylmethyl]acetamide (78 mg) and (Z)-N-[5(S)-3-[4-[(1α,5α,6α)-6-amino[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (35 mg).

(E)-form: MS (FAB⁺) m/z: 392 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₃FN₅O₄(MH⁺): calcd, 392.1734; found, 392.1750.

EXAMPLE 66 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-(methoxy)ethoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The mixture of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and crude 0-(2-methoxyethyl)hydroxylamine (prepared from N-(2-methoxyethoxy)phthalimide (442 mg)) in ethanol (5 mL) and dichloromethane (1 mL) was stirred at room temperature for

hours, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate: methanol=19:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-(methoxy)ethoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (172 mg).

MS (EI⁺) m/z: 434 (M⁺).

HRMS (EI⁺) for C₂₁H₂₇FN₄O₅(M⁺): calcd, 434.1965; found, 434.1923.

EXAMPLE 67 N-[5(S)-3-[4-[(1α,5α,6α)-6-[2-(Dimethylamino)ethoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(dimethylamino) ethoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (152 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg), crude O-(dimethylaminoethyl)hydroxylamine hydrochloride (prepared from N-(2-dimethylaminoethoxy)phthalimide (469 mg)), and sodium acetate (328 mg) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 447 (M⁺).

HRMS (EI⁺) for C₂₂H₃₀FN₅O₄ (M⁺): calcd, 447.2282; found, 447.2275.

EXAMPLE 68 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(Dimethylamino)propoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(dimethylamino) propoxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (176 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg), crude O-(dimethylaminopropyl)hydroxylamine hydrochloride (prepared from N-(2-dimethylaminopropoxy)phthalimide (497 mg)), and sodium acetate (328 mg) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 461 (M⁺).

HRMS (EI⁺) for C₂₃H₃₂FN₅O₄ (M⁺): calcd, 461.2438; found, 461.2414.

EXAMPLE 69 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-hydroxyethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-hydroxyethoxy) iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (149 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and crude O-(2-hydroxyethyl)hydroxylamine (prepared from N-(2-hydroxyethoxy)phthalimide (414 mg)) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 420 (M⁺).

HRMS (EI⁺) for C₂₀H₂₅FN₄O₅ (M⁺): calcd, 420.1809; found, 420.1778.

EXAMPLE 70 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(1-t-Butoxycarboxyl-1-methyl)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(1-t-butoxycarboxyl-1-methyl)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (280 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (200 mg) and crude O-[1-(1-t-butylcarbonyl-1-methyl)ethyl]hydroxylamine (prepared from N-[1-(1-t-butoxycarboxyl-1-methyl)ethoxy]phthalimide (611 mg)) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 518 (M⁺).

HRMS (EI⁺) for C₂₆H₃₅FN₄O₆ (M⁺): calcd, 518.2541; found, 518.2549.

EXAMPLE 71 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(1-Carboxyl-1-methyl ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(1-t-butoxycarboxyl-1-methyl)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (230 mg) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 18 hours, and then concentrated in vacuo. After addition of water to the residue, the resulting precipitates were collected by filtration, washed with water and ethyl acetate and, dried to give N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(1-carboxyl-1-methyl)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (149 mg).

MS (FAB⁺) m/z: 461 (M−H⁺).

HRMS (FAB⁺) for C₂₂H₂₆FN₄O₆ (M−H⁺): calcd, 461.1836; found, 461.1849.

EXAMPLE 72 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(5-tetrazolylmethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(5-tetrazolyl methoxy) iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (125 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (120 mg), crude O-[(5-tetrazolyl)methyl]hydroxylamine hydrochloride (prepared from N-[(5-tetrazolyl)methoxy]phthalimide (220 mg)), and sodium acetate (221 mg) in the same manner as described for EXAMPLE 66.

MS (FAB⁺) m/z: 459 (MH⁺).

HRMS (FAB⁺) for C₂₀H₂₄FN₈O₄(MH⁺): calcd, 459.1905; found, 459.1916.

EXAMPLE 73 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(N-(4-morpholinyl)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(N-(4-morpholinyl)imino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (175 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0.]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and 4-aminomorpholine (55 mg) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 445 (M⁺).

HRMS (EI⁺) for C₂₂H₂₈FN₅O₄ (M⁺): calcd, 445.2125; found, 445.2111.

EXAMPLE 74 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(2,3-Dihydroxy)propyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-(2,3-dihydroxy)propyloxy) iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (186 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg), O-[1-(2,3-dihydroxy)propyl]hydroxylamine hydrochloride (119 mg), and sodium acetate (136 mg) in the same manner as described for EXAMPLE 66.

MS (FAB⁺) m/z: 451 (MH⁺).

HRMS (FAB⁺) for C₂₁H₂₈FN₄O₆(MH⁺): calcd, 451.1993; found, 451.2013.

EXAMPLE 75 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(1,3-Dihydroxy)propyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(1,3-dihydroxy)propyloxy) iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (178 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg), O-[2-(1,3-dihydroxy)propyl]hydroxylamine hydrochloride (119 mg), and sodium acetate (136 mg) in the same manner as described for EXAMPLE 66.

MS (FAB⁺) m/z: 451 (MH⁺).

HRMS (FAB⁺) for C₂₁H₂₈FN₄O₆(MH⁺): calcd, 451.1993; found, 451.1978.

EXAMPLE 76 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(1-(2-(2-hydroxyethoxy))ethoxy) iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(1-(2-(2-hydroxy ethoxy))ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (184 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg), O-[2-(2-hydroxyethoxy)ethyl]hydroxylamine hydrochloride (131 mg), and sodium acetate (136 mg) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 465 (M⁺).

HRMS (EI⁺) for C₂₂H₃₀FN₄O₆ (M⁺): calcd, 465.2149; found, 465.2168.

EXAMPLE 77 N-[5(S)-3-[4-[(1α,5α,6α)-6-(Cyanomethyloxy)iminomethyl]-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-(cyanomethyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (168 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and crude O-(cyanomethyl)hydroxylamine (prepared from N-(cyanomethoxy)phthalimide (202 mg)) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 415 (M⁺).

HRMS (EI⁺) for C₂₀H₂₂FN₅O₄ (M⁺): calcd, 415.1656; found, 415.1637.

EXAMPLE 78 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide N-Oxide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (85.0 mg) in dichloromethane (3 mL) was added m-chloroperbenzoic acid (81.9 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. After addition of piperidine (120 mg, polymer bounded, 3.5 mmol/g resin), the mixture was stirred at room temperature for 30 min, and then added powdered sodium hydrogencarbonate (40 mg). Flash chromatography (silica, dichloromethane:methanol=4:1) of the mixture gave N-[5(S)-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide N-Oxide (79 mg).

MS (FAB⁺) m/z: 375 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₀FN₄O₄ (MH⁺): calcd, 375.1469; found, 375.1450.

EXAMPLE 79 N-[5(S)-3-[4-[(1α,5α,6α)-6-Ethenyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of dimsyl sodium in dimethyl sulfoxide (prepared from sodium hydride (60 mg) and dimethyl sulfoxide (1.5 mL)) was added a solution of methyltriphenylphosphonium bromide (536 mg) in dimethyl sulfoxide (1 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the resulting mixture was added a solution of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (361 mg) in dimethyl sulfoxide (1 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After quenching the reaction by the addition of water, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=20:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-ethenyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (310 mg).

MS (EI⁺) m/z: 359 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂FN₃O₃ (M⁺): calcd, 359.1645; found, 359.167°.

EXAMPLE 80 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-ethenyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (120 mg) in tetrahydrofuran (3 mL) was added 9-BBN (0.5 M solution in tetrahydrofuran, 0.8 mL) at 0° C., and the mixture was stirred at room temperature for 6 hours. Further amount of 9-BBN (0.5 M solution in tetrahydrofuran, 0.8 mL) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 12 hours. Hydrogen peroxide (30%, 0.1 mL) and 2 N sodium hydroxide solution (0.5 mL) were added to the mixture at 0° C., and the mixture was stirred at room temperature for 30 min. After addition of 5% sodium thiosulfate solution, the mixture was exrtacted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=10:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (44 mg).

MS (EI⁺) m/z: 377 (M⁺).

HRMS (EI⁺) for C₁₉H₂₄FN₃O₄ (M⁺): calcd, 377.1751; found, 377.1747.

EXAMPLE 81 N-[5(S)-3-[4-[(1α,5α,6α)-6-[1-(2-t-Butyldiphenylsilyloxy-1-hydroxy)ethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Step 1.

N-[5(S)-3-[4-[(1α,5α,6α)-6-(1,2-Dihydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-ethenyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (280 mg) in acetonitrile (3 mL), acetone (3 mL), and water (3 mL) was added N-methylmorpholine N-oxide (NMO, 137 mg) and osmium oxide (capsuled, 10% w/w, 792 mg), and the mixture was stirred at room temperature for 3 weeks. After insoluble materials were filtered off, the filtrate was concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=5:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(1,2-dihydroxyethyl)-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (147 mg).

Step 2.

N-[5(S)-3-[4-[(1α,5α,6α)-6-[1-(2-t-Butyldiphenylsilyloxy-1-hydroxy)ethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-(1,2-dihydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (100 mg) in DMF (2 mL) and dichloromethane (2 mL) was added (4-dimethylamino)pyridine (93 mg) and t-butyldiphenylsilylchloride (139 mg) at room temperature, and the mixture was stirred at the same temperature for 30 min. After quenching the reaction by the addition of saturated sodium hydrogencarbonate solution, the mixture was extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=15:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[1-(2-t-butyldiphenylsilyloxy-1-hydroxy)ethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (144 mg).

MS (EI⁺) m/z: 631 (M⁺).

HRMS (EI⁺) for C₃₅H₄₂FN₃O₅Si (M⁺): calcd, 631.2878; found, 631.2816.

EXAMPLE 82 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(t-Butyldiphenylsilyl)oxy)acetyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-[(2-(t-butyldiphenyl silyl)oxy)acetyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (129 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-[1-(2-t-butyldiphenylsilyloxy-1-hydroxy)ethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (142 mg) in the same manner as described for EXAMPLE 22.

MS (EI⁺) m/z: 629 (M⁺).

HRMS (EI⁺) for C₃₅H₄₀FN₃O₅Si (M⁺): calcd, 629.2721; found, 629.2689.

EXAMPLE 83 N [5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxyacetyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-[1-(2-t-butyldiphenylsilyloxy-1-hydroxy)ethyl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (129 mg) in tetrahydrofuran (3 mL) was added acetic acid (36.9 mg) and tetrabutylammonium fluoride (TBAF, 1 M solution in tetrahydrofuran, 410 μL) at room temperature, and the mixture was stirred for 1 hour. After quenching the reaction by the addition of saturated ammonium chloride solution and brine, the mixture was extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=9:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxyacetyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (67 mg).

MS (EI⁺) m/z: 391 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂FN₃O₅ (M⁺): calcd, 391.1543; found, 391.1500.

EXAMPLE 84 N-[5(S)-3-[3-Fluoro-4-[f 1 (1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

5(R)-3-[4-[(1α,5α,6α)-6-t-Butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (200 mg) was prepared from 1-benzyloxycarbonylamino-4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorobenzene (320 mg) and (R)-glycidyl butyrate (101 mg) in the same manner as described for EXAMPLE 9.

MS (EI⁺) m/z: 22 (M⁺).

HRMS (EI⁺) for C₂₁H₃₁FN₂O₄Si (M⁺): calcd, 422.2037; found, 422.2059.

Step 2.

5(R)-Azidomethyl-3-[4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one.

The title compound 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (202 mg) was prepared from (R)-3-[4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (190 mg) in the same manner as described for EXAMPLE 9.

MS (EI⁺) m/z: 447 (M⁺).

HRMS (EI⁺) for C₂₁H₃₀FN₅O₃Si (M⁺): calcd, 447.2102; found, 447.2119.

Step 3.

N-[5(S)-3-[4-[(1α,5α,6α)-6-t-Butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide was prepared from the above crude 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-t-butyldimethyl silyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one in the same manner as described for EXAMPLE 9.

Step 4.

N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a solution of the above crude N-[5(S)-3-[4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (TBAF, 1 M solution in tetrahydrofuran, 500 μL) at room temperature, and the mixture was stirred for 30 min. After quenching the reaction by the addition of saturated ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=9:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (94.0 mg).

MS (EI⁺) m/z: 349 (M⁺).

HRMS (EI⁺) for C₁₇H₂₀FN₃O₄(M⁺): calcd, 349.1438; found, 349.1455.

EXAMPLE 85 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylthio)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylthio) ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (172 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and crude O-(2-methylthio)ethylhydroxylamine (prepared from N-(2-methylthioethoxy) phthalimide (197 mg)) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 450 (M⁺).

HRMS (EI⁺) for C₂₁H₂₇FN₄O₄S (M⁺): calcd, 450.1737; found, 450.1736.

EXAMPLE 86 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylsulfinyl)ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylsulfinyl) ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (188 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and crude O-(2-methylsulfinyl)ethylhydroxylamine (prepared from N-(2-methyl sulfinylethoxy) phthalimide (210 mg)) in the same manner as described for EXAMPLE 66.

MS (FAB⁺) m/z: 467 (MH⁺).

HRMS (FAB⁺) for C₂₁H₂₈FN₄O₅S (MH⁺): calcd, 467.1764; found, 467.1760.

EXAMPLE 87 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylsulfonyl)ethoxy)iminomethyl]3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(1-(2-methylsulfonyl) ethoxy)iminomethyl]-3-azabicyclo[3.1. O]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (194 mg) was prepared from N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) and crude O-(2-methylsulfonyl)ethylhydroxylamine (prepared from N-(2-methyl sulfonylethoxy)phthalimide (224 mg)) in the same manner as described for EXAMPLE 66.

MS (FAB⁺) m/z: 482 (M⁺).

HRMS (FAB⁺) for C₂₁H₂₇FN₄O₆S (M⁺): calcd, 482.1635; found, 482.1656.

EXAMPLE 88 N-[5(S)-3-[5-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

N-[5(S)-3-[5-[(1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide

The mixture of N-[5(S)-3-(5-bromopyridin-2-yl)-2-oxooxazolidin-5-ylmethyl]acetamide (170 mg), (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (334 mg), tetrakis(triphenyl phosphine)palladium(0) (31.3 mg), and tri-potassium phosphate (n-hydrate, 345 mg) in dioxane (10 mL) and water (2 mL) was heated at 80° C. for 1 hour, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=19:1) of the residue gave N-[5(S)-3-[5-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (291 mg).

Step 2.

N-[5(S)-3-[5-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[5-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (103 mg) was prepared from N-[3(S)-3-[5-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (278 mg) in the same manner as described for EXAMPLE 83.

MS (EI⁺) m/z: 343 (M⁺).

HRMS (EI⁺) for C₁₈H₂₁N₃O₄ (M): calcd, 343.1532; found, 343.1522.

EXAMPLE 89 N-[5(S)-3-[5-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[5-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (74 mg) was prepared from N-[5(S)-3-[5-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-2-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (90 mg) in the same manner as described for Example 49.

MS (EI⁺) an/z: 338 (M⁺).

HRMS (EI⁺) for C₁₈H₁₈N₄O₃ (M⁺): calcd, 338.1379; found, 338.1387.

EXAMPLE 90 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The mixture of N-[5(S)-3-[3,5-difluoro-4-[(trifluoromethanesulfonyl)oxy]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (601 mg), (1α,5α,6α)-6-[(t-butyldiphenylsilyl) oxy]methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (682 mg), tetrakis(triphenylphosphine)palladium(0) (166 mg), and 2 M sodium carbonate solution (2.88 mL) in dioxane (28 mL) was heated at 100° C. for 2 hours, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=19:1) of the residue gave N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.11.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-hydroxy methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (467 mg) was prepared from the above N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide in the same manner as described for Example 83.

MS (EI⁺) m/z: 378 (M⁺).

HRMS (EI⁺) for C₁₉H₂₀F₂N₂O₄ (M⁺): calcd, 378.1391; found, 378.1381.

EXAMPLE 91 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (45 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-hydroxymethyl bicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (378 mg) in the same manner as described for Example 49.

MS (EI⁺) m/z: 373 (M⁺).

HRMS (EI⁺) for C₁₉H₁₇F₂N₃O₃(M⁺): calcd, 373.1238; found, 373.1268.

EXAMPLE 92 N-[5(S)-3-[4-[(1α,5α,6α)-6-(1-Cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one

To a solution of 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl) oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (4.80 g) in dichloromethane (80 mL) was added imidazole (1.21 g), (4-dimethylamino)pyridine (721 mg), and triisopropylsilylchloride (2.73 g) at 0° C., and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water, 5% hydrochloric acid, and brine. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo to give 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydro pyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one.

To a solution of the crude 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetra hydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one in methanol (67 mL) was added p-toluenesulfonic acid hydrate (674 mg), and the mixture was stirred at room temperature for 8 hours. After quenching the reaction by the addition of saturated sodium hydrogencarbonate solution and brine, the mixture was extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane ethyl acetate=2:3) of the residue gave 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxy methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (5.31 g).

MS (EI⁺) m/z: 478 (M⁺).

HRMS (EI⁺) for C₂₅H₃₉FN₂O₄Si (M⁺): calcd, 478.2663; found, 478.2667.

Step 2.

5(R)-3-[4-[(1α,5α,6α)-6-Bromomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-bromomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (3.70 g) was prepared from 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (3.40 g) in the same manner as described for EXAMPLE 25.

MS (EI⁺) m/z: 540 (M⁺).

HRMS (EI⁺) for C₂₅H₃₈BrFN₂O₃Si (M⁺): calcd, 540.1819; found, 540.1848.

Step 3.

5(R-3-[4-[(1α,5α,6α)-6-Cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (3.25 g) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-bromomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (3.70 g) in the same manner as described for EXAMPLE 26.

MS (EI⁺) m/z: 487 (M⁺).

HRMS (EI⁺) for C₂₆H₃₈FN₃O₃Si (M⁺): calcd, 487.2666; found, 487.2674.

Step 4.

5(R)-3-[4-[(1α,5α,6α)-6-(1-Cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one and 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one.

To a solution of 5(R)-3-[4-[(1α,5α,6α)-6-cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (1.10 g) and methyliodide (309 μL) in tetrahydrofuran (25 mL) was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 9.92 mL) at 0° C. for 15 min, and the mixture was stirred at the same temperature for 1 hour. After quenching the reaction by the addition of saturated ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=7:3) of the residue gave 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (326 mg) and 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (758 mg).

5(R)-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one: MS (EI⁺) m/z: 501 (M⁺).

HRMS (EI⁺) for C₂₇H₄₀FN₃O₃Si M⁺): calcd, 501.2823; found, 501.2785.

5(R)-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one: MS (EI⁺) m/z: 515 (M⁺).

HRMS (EI⁺) for C₂₈H₄₂FN₃O₃Si (M⁺): calcd, 515.2979; found, 515.2999.

Step 5.

5(R)-3-[4-[(1α,5α,6α)-6-(1-Cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (430 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (720 mg) in the same manner as described for EXAMPLE 83.

MS (EI⁺) m/z: 345 (M⁺).

HRMS (EI⁺) for C₁₈H₂₀FN₃O₃ (M⁺): calcd, 345.1489; found, 345.1528.

Step 6.

5(R)-Azidomethyl-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one

The title compound 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (204 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoro phenyl]-5-hydroxymethyloxazolidin-2-one (218 mg) in the same manner as described for Example 9.

MS (EI⁺) m/z: 370 (M⁺).

HRMS (EI⁺) for C₁₈H₁₉FN₆O₂ (M⁺): calcd, 370.1554; found, 370.1560.

Step 7.

N-[5(S)-3-[4-[(1α,5α,6α)-6-(1-Cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (195 mg) was prepared from 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-(1-cyanoethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (197 mg) in the same manner as described for Example 9.

MS (EI⁺) m/z: 386 (M⁺).

HRMS (EI⁺) for C₂₀H₂₃FN₄O₃ (M⁺): calcd, 386.1754; found, 386.1738.

EXAMPLE 93 N-[5(S)-3-[4-[(1α,5α,6α)-6-(1-Cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

5(R)-3-[4-[(1α,5α,6α)-6-(1-Cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (175 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicycl[3.1.0]exan-3-yl]-3-fluorophenyl]-5-[(triisopropylsilyl)oxy]methyloxazolidin-2-one (277 mg) in the sane manner as described for EXAMPLE 83.

MS (EI⁺) m/z: 359 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂FN₃O₃ (M⁺): calcd, 359.1645; found, 359.1629.

Step 2.

5(R)-Azidomethyl-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one.

The title compound 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (159 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (166 mg) in the same manner as described for Example 9.

MS (EI⁺) m/z: 384 (M⁺).

HRMS (EI⁺) for C₁₉H₂₁FN₆O₂ (M⁺): calcd, 384.1710; found, 384.1721.

Step 3.

[5(S)-3-[4-[(1α,5α,6α)-6-(1-Cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg) was prepared from 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-(1-cyano-1-methylethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]oxazolidin-2-one (152 mg) in the same manner as described for Example 9.

MS (EI⁺) m/z: 400 (M⁺).

HRMS (EI⁺) for C₂₁H₂₅FN₄O₃ (M⁺): calcd, 400.1911; found, 400.1925.

EXAMPLE 94 N-[5(S)-3-[6-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

N-[5(S)-3-[6-[(1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[6-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl) xy]methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (1.30 g) was prepared from N-[5(S)-3-(6-bromopyridin-3-yl)-2-oxooxazolidin-5-ylmethyl]acetamide (717 mg) and (1α,5α,6α)-6-[(t-butyldiphenyl silyl)oxy]methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (1.30 g) in the same manner as described for Example 88.

MS (FAB⁺) m/z: 582 (MH⁺).

HRMS (FAB⁺) for C₃₄H₄₀N₃O₄Si (MH⁺): calcd, 582.2788; found, 582.2783.

Step 2.

N-[5(S)-3-[6-[(1α,5α,6α) 5-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[6-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (658 mg) was prepared from N-[5(S)-3-[6-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (1.30 g) in the same manner as described for EXAMPLE 83.

MS (EI⁺) m/z: 343 (M⁺).

HRMS (EI⁺) for C₁₈H₂₁N₃O₄(M⁺): calcd, 343.1532; found, 343.1547.

EXAMPLE 95 N-[5(S)-3-[6-[(1α,5α,6α)-6-(Hydroxyimino)methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[6-[(1α,5α,6α)-6-(hydroxyimino) methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (343 mg) was prepared from N-[5(S)-3-[6-[(1α,5α,6α)-6-hydroxymethyl bicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (400 mg) in the same manner as described for Example 22 and 66.

MS (FAB⁺) m/z: 357 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₁N₄O₄ (MH⁺): calcd, 357.1563; found, 357.1577.

EXAMPLE 96 N-[5(S)-3-[6-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[6-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (210 mg) was prepared from N-[5(S)-3-[6-[(1α,5α,6α)-6-(hydroxyimino)methylbicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (243 mg) in the same manner as described for Example 49.

MS (EI⁺) m/z: 338 (M⁺).

HRMS (EI⁺) for C₁₈H₁₈N₄O₃ (M⁺): calcd, 338.1379; found, 338.1403.

EXAMPLE 97 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (380 mg) in dioxane (2 mL) and toluene (2 mL) was added Lawesson's reagent (300 mg), and the mixture was heated at 80° C. for 1, hour. Flash chromatography (silica, hexane:ethyl acetate=2:3) of the mixture gave N-[5(S)-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-yl methyl]thioacetamide (280 mg).

MS (FAB⁺) m/z: 375 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₀FN₄O₂S (MH⁺): calcd, 375.1291; found, 375.1292.

EXAMPLE 98 N-[5(S)-3-[6-[(1α,5α,6α)-6-Cyanobicyclo[3.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]thioacetamide

The title compound N-[5(S)-3-[6-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]thioacetamide (58.5 mg) was prepared from N-[5(S)-3-[6-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]pyridin-3-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (165 mg) in the same manner as described for Example 97.

MS (FAB⁺) m/z: 355 (MH⁺).

HRMS (FAB⁺) for C₁₈H₁₉N₄O₂S (MH⁺): calcd, 355.1229; found, 355.1268.

EXAMPLE 99 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide (112 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (170 mg) in the same manner as described for Example 97.

MS (FAB⁺) m/z: 354 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₀N₃O₂S (MH⁺): calcd, 354.1276; found, 354.1272.

EXAMPLE 100 N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

Step 1.

5(R)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one.

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one (3.15 g) was prepared from 4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-benzyloxycarbonylamino-3,5-difluorobenzene (4.60 g) in the same manner as described for Example 9.

MS (FAB⁺) m/z: 516 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₂F₂N₃O₅ (MH⁺): calcd, 516.2310; found, 516.2332.

Step 2.

N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo [3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxy carbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (849 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxy methyloxazolidin-2-one (1.00 g) in the same manner as described for Example 9.

MS (FAB⁺) m/z: 557 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₅F₂N₄O₅ (MH⁺): calcd, 557.2576; found, 557.2586.

EXAMPLE 101 N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (220 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo [3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (590 mg) in the same manner as described for Example 1 and 8.

MS (EI⁺) m/z: 366 (M⁺).

HRMS (EI⁺) for C₁₇H₂₀F₂N₄O₃ (M⁺): calcd, 366.1503; found, 366.1543.

EXAMPLE 102 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Step 1.

5(R)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one.

The title compound 5(R)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl) oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (5.47 g) was prepared from 1-benzyloxycarbonylamino-3,5-difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (7.50 g) in the same manner as described for EXAMPLE 9.

Step 2.

N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (4.65 g) was prepared from 5(R)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxy methyloxazolidin-2-one (5.36 g) in the same manner as described for EXAMPLE 9.

⁺H NMR (CDCl₃) δ 1.19-1.87 (m, 9H), 2.02 (s, 3H), 3.41-4.77 (m, 14H), 6.17 (t, J=5.9 Hz, 1H), 7.01 (d, J=1.7 Hz, 1H).

Step 3.

N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (3.00 g) was prepared from 1-benzyloxy carbonylamino-3,5-difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydro pyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (7.50 g) in the same manner as described for EXAMPLE 13.

MS (FAB⁺) m/z: 381 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₁F₂N₃O₄ (MH⁺): calcd, 381.1500; found, 381.1518.

EXAMPLE 103 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (281 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-hydroxymethyl bicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (300 mg) in the same manner as described for EXAMPLE 22.

MS (EI⁺) m/z: 379 (M⁺).

HRMS (EI⁺) for C₁₈H₂₀FN₃O₄ (M⁺): calcd, 379.1344; found, 379.1311.

EXAMPLE 104 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(hydroxyimino) methyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (261 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (274 mg) in the same manner as described for EXAMPLE 4.

MS (FAB⁺) m/z: 395 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₁F₂N₄O₄ (MH⁺): calcd, 395.1531; found, 395.1538.

EXAMPLE 105 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (147 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (155 mg) in the same manner as described for EXAMPLE 46.

MS (EI⁺) m/z: 376 (M⁺).

HRMS (EI⁺) for C₁₈H₁₈F₂N₄O₃(M⁺): calcd, 376.1347; found, 376.1328.

EXAMPLE 106 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (69 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-hydroxy methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (110 mg) in the same manner as described for EXAMPLE 25 and 26.

MS (EI⁺) m/z: 390 (M⁺).

HRMS (EI⁺) for C₁₉H₂₀F₂N₄O₃ (M⁺): calcd, 390.1503; found, 390.1532.

EXAMPLE 107 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(1-(2,3-Dihydroxy)propyloxy) iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(1-(2,3-dihydroxy)propyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]2-oxooxazolidin-5-ylmethyl]acetamide (163 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (200 mg), O-[1-(2,3-dihydroxy)propyl]hydroxylamine hydrochloride (314 mg), and sodium acetate (260 mg) in the same manner as described for EXAMPLE 66.

MS (FAB⁺) m/z: 469 (MH⁺).

HRMS (FAB⁺) for C₂₁H₂₇F₂N₄O₆(MH⁺): calcd, 469.1899; found, 469.1885.

EXAMPLE 108 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(2-hydroxyethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(2-hydroxyethoxy) iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (210 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (202 mg) and crude O-(2-hydroxyethyl)hydroxylamine (prepared from N-(2-hydroxyethoxy)phthalimide (507 mg)) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 438 (M⁺).

HRMS (EI⁺) for C₂₀H₂₄F₂N₄O₅ (M⁺): calcd, 438.1715; found, 438.1735.

EXAMPLE 109 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(1-(2-(2-hydroxyethoxy))ethoxy iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(1-(2-(2-hydroxy ethoxy))ethoxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (345 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (300 mg), crude O-[2-(2-hydroxyethoxy)ethyl]hydroxylamine hydrochloride (prepared from N-[2-(2 hydroxyethoxy)ethoxy]phthalimide (766 mg)), and sodium acetate (500 mg) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 482 (M⁺).

HRMS (EI⁺) for C₂₂H₃₀FN₄O₆ (M⁺): calcd, 482.1977; found, 482.1986.

EXAMPLE 110 N-[5(S)-3-[3,5-Difluoro-4-[(1α,5α,6α)-6-[(2-(1,3-dihydroxy)propyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-[(2-(1,3-dihydroxy) propyloxy)iminomethyl]-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (220 mg) was prepared from N-[5(S)-3-[3,5-difluoro-4-[(1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (198 mg), O-[2-(1,3-dihydroxy)propyl]hydroxylamine hydrochloride (173 mg), and sodium acetate (195 mg) in the same manner as described for EXAMPLE 66.

MS (EI⁺) m/z: 468 (M⁺).

HRMS (EI⁺) for C₂₁H₂₆F₂N₄O₆ (M⁺): calcd, 468.1820; found, 468.1823.

EXAMPLE 111 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl) oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (370 mg) was prepared from N-[5(S)-3-[4-(trimethylstannyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (619 mg) and (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-[(trifluoromethanesulfonyl)oxy]bicyclo[3.1.0]hex-2-ene (646 mg) in the same manner as described for EXAMPLE 47.

MS (FAB⁺) m/z: 581 (MH⁺).

+H NMR (CDCl₃) δ 1.05 (s, 9H), 1.58 (s, 1H), 1.82 (m, 1H), 2.02 (s, 3H), 2.67 (d, J=17.1 Hz, 1H), 2.93 (dd, J=17.1, 7.8 Hz, 1H), 3.52-4.07 (m, 7H), 4.77 (m, 1H), 6.04 (m, 1H), 6.27 (d, J=2.0 Hz, 1H), 7.28-7.70 (m, 14H).

EXAMPLE 112 N-[5(S)-3-[4-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (174 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (370 mg) in the same manner as described for EXAMPLE 48.

MS (EI⁺) m/z: 342 (M⁺).

¹H NMR (DMSO-d₆) δ 0.63 (m, 1H), 1.66 (m, 1H), 1.89 (s, 3H), 1.91 (m, 1H), 2.72 (d, J=16.6 Hz, 1H), 2.96 (dd, J=16.6, 7.8 Hz, 1H), 3.25-3.48 (m, 4H), 3.79 (dd, J=8.8 Hz, 6.8 Hz, 1H), 4.16 (t, J=8.8 Hz, 1H), 4.58 (t, J=5.9 Hz, 1H), 4.77 (m, 1H), 6.48 (d, J=2.0 Hz, 1H), 7.45 (d, J=9.3 Hz, 2H), 7.52 (d, J=9.3 Hz, 2H), 8.31 (t, J=5.9 Hz, 1H).

EXAMPLE 113 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (104 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (168 mg) in the same manner as described for EXAMPLE 49.

MS (EI⁺) m/z: 337 (M⁺).

HRMS (EI⁺) for C₁₉H₁₉N₃O₃ (M⁺): calcd, 337.1426; found, 337.1461.

EXAMPLE 114 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (111 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluo ophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (123 mg) in the same manner as described for EXAMPLE 8.

MS (FAB⁺) m/z: 358 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₁FN₃O₃ (MH⁺): calcd, 358.1567; found, 358.1560.

EXAMPLE 115 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide (114A) and N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-thiocarbamoylbicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (114B).

The title compounds N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide (22 mg) and N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-thiocarbamoylbicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (47 mg) were prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (99 mg) in the same manner as described for EXAMPLE 97.

114A: MS (FAB⁺) m/z: 374 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₁FN₃O₂S (MH⁺): calcd, 374.1339; found, 374.1342.

114B: MS (FAB⁺) m/z: 408 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₃FN₃O₂S₂ (MH⁺): calcd, 408.1216; found, 408.1224.

EXAMPLE 116 5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one.

The title compound 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl) oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyl oxazolidin-2-one (889 mg) was prepared from 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyl oxazolidin-2-one (702 mg) in the same manner as described for EXAMPLE 16.

MS (EI⁺) m/z: 473 (M⁺).

HRMS (EI⁺) for C₂₄H₂₈FN₃O₆ (M⁺): calcd, 473.1962; found, 473.1975.

EXAMPLE 117 5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one

The title compound 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (645 mg) was prepared from 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (810 mg) in the same manner as described for EXAMPLE 13.

MS (EI⁺) m/z: 389 (M⁺).

HRMS (EI⁺) for C₁₉H₂₀FN₃O₅(M⁺): calcd, 389.1387; found, 389.1397.

EXAMPLE 118 5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-[(isoxazolyl-3-yl)oxy]methyl-3-azabicyclo [3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one.

The title compound 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-[(isoxazolyl-3-yl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (200 mg) was prepared from 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (260 mg) in the same manner as described for EXAMPLE 16.

MS (EI⁺) m/z: 456 (M⁺).

HRMS (EI⁺) for C₂₂H₂₁FN₄O₆(M⁺): calcd, 456.1445; found, 456.1446.

EXAMPLE 119 5(R)-3-[3-Fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one

The title compound 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (110 mg) was prepared from 5(R)-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (200 mg) in the same manner as described for PREPARATIVE EXAMPLE 5.

MS (EI⁺) m/z: 403 (M⁺).

HRMS (EI⁺) for C₂₀H₂₂FN₃O₅ (M⁺): calcd, 403.1543; found, 403.1536.

EXAMPLE 120 5(R)-3-[4-[(1α,5α,6α)-6-(t-Butoxycarbonyl amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yloxy]methyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (322 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (306 mg) in the same manner as described for EXAMPLE 16.

MS (EI⁺) m/z: 474 (M⁺).

HRMS (EI⁺) for C₂₃H₂₇FN₄O₆(M⁺): calcd, 474.1915; found, 474.1919.

EXAMPLE 121 5(R)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (98 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (166 mg) in the same manner as described for EXAMPLE 64.

MS (EI⁺) m/z: 374 (M⁺).

HRMS (EI⁺) for C₁₈H₁₉FN₄O₄(M⁺): calcd, 374.1390; found, 374.1400.

EXAMPLE 122 5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one

The a suspension of 5(R)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (178 mg), 3-N-(t-butoxycarbonyl)amino-1,2,4-oxadiazole (157 mg), and tetramethylazodicarboxamide (195 mg) in benzene (36 mL) was added tributylphosphine (229 mg), and the mixture was heated at 60° C. for 49 hours. After insoluble materials were filtered off, the filtrate was concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=4:5) of the residue gave 5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one (207 mg).

MS (EI⁺) m/z: 481 (M⁺).

⁺H NMR (CDCl₃) δ 0.95 (t, J=2.4 Hz, 1H), 1.54 (s, 9H), 2.37 (m, 1H), 2.70 (m, 1H), 2.91 (d, J=17.6 Hz, 1H), 3.19 (dd, J=17.6, 6.4 Hz, 1H), 3.85 (dd, J=9.3, 5.9 Hz, 1H), 4.07-4.15 (m, 2H), 4.32 (dd, J=14.7, 6.8 Hz, 1H), 4.99 (m, 1H), 6.45 (s, 1H), 7.17-7.43 (m, 3H), 8.59 (s, 1H).

EXAMPLE 123 5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one (118 mg) was prepared from 5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyl oxazolidin-2-one (185 mg) in the same manner as described for EXAMPLE 64.

MS (EI⁺) m/z: 381 (M⁺).

HRMS (EI⁺) for C₁₉H₁₆FN₅O₃(M⁺): calcd, 381.1237; found, 381.1241.

EXAMPLE 124 5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one

Step 1.

5(S)-3-[4-[(1α,5α,6α)-6-(t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyloxazolidin-2-one (276 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (256 mg) and 3-N-(t-butoxycarbonyl)aminoisoxazole (174 mg) in the same manner as described for EXAMPLE 122.

MS (FAB⁺) nz/z: 574 (MH⁺).

Step 2.

5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one (124 mg) was prepared from 5(S)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyl oxazolidin-2-one (272 mg) in the same manner as described for EXAMPLE 64.

MS (FAB⁺) m/z: 374 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₁FN₅O₃ (MH⁺): calcd, 374.1628; found, 374.1605.

EXAMPLE 125 5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one.

Step 1.

5(S)-3-[4-[(1α,5α,6α)-6-(t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one (234 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-hydroxymethyl oxazolidin-2-one (280 mg) and 3-N-(t-butoxycarbonyl)amino-1,2,4-oxadiazole (191 mg) in the same manner as described for EXAMPLE 122.

MS (FAB⁺) m/z: 575 (MH⁺).

Step 2.

5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one (87 mg) was prepared from 5(S)-3-[4-[(1α,5α,6α)-6-(t-butoxycarbonyl)amino-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyl oxazolidin-2-one (234 mg) in the same manner as described for EXAMPLE 64.

MS (FAB⁺) m/z: 375 (MH⁺).

HRMS (FAB⁺) for C₁₇H₂₀FN₆O₃ (MH⁺): calcd, 375.1581; found, 375.1583.

EXAMPLE 126 5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one

Step 1.

5(R)-3-[4-[(1α,5α,6α)-6-(N-Benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl-N-t-butylcarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one in the same manner as described for EXAMPLE 1.

MS (FAB) m/z: 416 (MH⁺).

HRMS (FAB) for C₂₂H₂₄F₂N₃O₃ (MH⁺): calcd, 416.1786; found, 416.1820.

Step 2.

5(R)-3-[4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one (2.44 g) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(N-benzyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one (3.59 g) in the same manner as described for EXAMPLE 8 and REFFERENCE EXAMPLE 21.

MS (FAB) m/z: 426 (MH⁺).

HRMS (FAB⁺) for C₂₀H₂₆F₂N₃O₅ (MH⁺): calcd, 426.1841; found, 426.1805.

Step 3.

5(S)-3-[4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one (320 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one (255 mg) and 3-N-(t-butoxycarbonyl) amino-1,2,4-oxadiazole (167 mg) in the same manner as described for EXAMPLE 122.

MS (EI⁺) m/z: 592 (M⁺).

HRMS (EI⁺) for C₂₇H₃₄F₂N₆O₇ (M⁺): calcd, 592.2457; found, 592.2481.

Step 4.

5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one (142 mg) was prepared from 5(S)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one (466 mg) in the same manner as described for EXAMPLE 64.

MS (FAB⁺) m/z: 393 (MH⁺).

HRMS (FAB⁺) for C₁₇H₁₉F₂N₆O₃ (MH⁺): calcd, 393.1487; found, 393.1491.

EXAMPLE 127 5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one

Step 1.

5(S)-3-[4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyl oxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyloxazolidin-2-one (785 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluoro phenyl]-5-hydroxymethyloxazolidin-2-one (596 mg) and 3-N-(t-butoxycarbonyl) aminoisoxazole (387 mg) in the same manner as described for EXAMPLE 122.

MS (EI⁺) m/z: 591 (M⁺).

HRMS (EI⁺) for C₂₈H₃₅F₂N₅O₇ (M⁺): calcd, 591.2505; found, 591.2482.

Step 2.

5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[(isoxaxolyl-3-yl)amino]methyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one (277 mg) was prepared from 5(S)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]amino methyloxazolidin-2-one (820 mg) in the same manner as described for EXAMPLE 64.

MS (EI⁺) m/z: 391 (M⁺).

HRMS (EI⁺) for C₁₈H₁₉F₂N₅O₃ (M⁺): calcd, 391.1456; found, 391.1480.

EXAMPLE 128 5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one

Step 1.

5(S)-3-[4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyloxazolidin-2-one (415 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.11.0]hexan-3-yl]phenyl]-5-hydroxymethyl oxazolidin-2-one (405 mg) and 3-N-(t-butoxycarbonyl)aminoisoxazole (287 mg) in the same manner as described for EXAMPLE 122.

MS (EI⁺) m/z: 555 (M⁺).

HRMS (EI⁺) for C₂₈H₃₇N₅O₇ (M⁺): calcd, 555.2693; found, 555.2686.

Step 2.

5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one (173 mg) was prepared from 5(S)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyloxazolidin-2-one (415 mg) in the same manner as described for EXAMPLE 64.

MS (EI⁺) m/z: 355 (M⁺).

HRMS (EI⁺) for C₁₈H₂₁N₅O₃ (M⁺): calcd, 355.1644; found, 355.1618.

EXAMPLE 129 5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one

Step 1.

5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one.

The title compound 5(S)-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (238 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (180 mg) and 3-N-(t-butoxycarbonyl)amino-1,2,4-oxadiazole (135 mg) in the same manner as described for EXAMPLE 122.

MS (EI⁺) m/z: 463 (M⁺).

HRMS (EI⁺) for C₂₄H₂₅N₅O₅ (M⁺): calcd, 463.1856; found, 463.1840.

Step 2.

5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)]aminomethyloxazolidin-2-one (123 mg) was prepared from 5(S)-5-[N-(t-butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]aminomethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (200 mg) in the same manner as described for EXAMPLE 64.

MS (EI⁺) m/z: 363 (M⁺).

HRMS (EI⁺) for C₁₉H₁₇N₅O₃ (M⁺): calcd, 363.1331; found, 363.1329.

EXAMPLE 130 5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one

Step 1

5(S)-5-[N-(t-Butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one.

The title compound 5(S)-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (280 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (180 mg) and 3-N-(t-butoxycarbonyl)aminoisoxazole (134 mg) in the same manner as described for EXAMPLE 122.

MS (EI⁺) m/z: 462 (M⁺).

HRMS (EI⁺) for C₂₅H₂₆N₄O₅ (M⁺): calcd, 462.1903; found, 462.1917.

Step 2.

5(S)-3-[4-[(1α,5α,6α)-6-Cyano-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one

The title compound 5(S)-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-[(isoxazolyl-3-yl)amino]methyloxazolidin-2-one (147 mg) was prepared from 5(S)-5-[N-(t-butoxycarbonyl)-N-(isoxazolyl-3-yl)]aminomethyl-3-[4-[(1α,5α,6α)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one (260 mg) in the same manner as described for EXAMPLE 64.

MS (EI⁺) m/z: 362 (M⁺).

HRMS (EI⁺) for C₂₀H₁₈N₄O₃ (M⁺): calcd, 362.1379; found, 362.1375.

EXAMPLE 131 5(R)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-[(isoxazolyl-3-yl)oxy]methyloxazolidin-2-one (181 mg) was prepared from 5(R)-3-[4-[(1 (1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (180 mg) and 3-hydroxyisoxazole (67 mg) in the same manner as described for EXAMPLE 16.

MS (EI⁺) m/z: 363 (M⁺).

HRMS (EI⁺) for C₂₀H₁₇N₃O₄ (M⁺): calcd, 363.1219; found, 363.1207.

EXAMPLE 132 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(N-Cyano-1-iminoethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (293 mg) in methanol (5 mL) was added N-cyano-O-methylacetimidate (118 mg), and the mixture was stirred at room temperature for 6 days. The resulting precipitates were collected by filteration, washed with cold methanol to give N-[5(S)-3-[4-[(1α,5α,6α)-6-[(N-cyano-1-iminoethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (89 mg).

MS (FAB⁺) m/z: 433 (MH⁺).

HRMS (FAB⁺) for C₂₀H₂₃F₂N₆O₃ (MH⁺): calcd, 433.1800; found, 433.1795.

EXAMPLE 133 N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-Amino-4-cyano-1,3-oxazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-carboxyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (180 mg) in pyridine (10 mL) was added aminomalononitrile toluenesulfonate (362 mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (366 mg), and the mixture was stirred at room temperature for 5 days. After addition of water to the mixture, the resulting precipitates were collected by filtration, washed with water and dried in air. Flash chromatography (silica, ethyl acetate:methanol=9:1) of the precipitates gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-amino-4-cyano-1,3-oxazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (145 mg).

MS (FAB⁺) m/z: 441 (MH⁺).

HRMS (FAB⁺) for C₂₁H₂₂N₆O₄ (MH⁺): calcd, 441.1687; found, 441.1684.

EXAMPLE 134 N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-Amino-4-cyano-1,3-oxazol-2-yl)bicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Step 1.

N-[5(S)-3-[4-[(1α,5α,6α)-6-Carboxybicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-carboxybicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (175 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-formylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (200 mg) in the same manner as described for EXAMPLE 23.

Step 2.

N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-Amino-4-cyano-1,3-oxazol-2-yl)bicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-(5-amino-4-cyano-1,3-oxazol-2-yl)bicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (147 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-carboxybicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (175 mg) and aminomalononitrile toluenesulfonate (355 mg) in the same manner as described for EXAMPLE 133.

MS (FAB⁺) m/z: 438 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₁FN₅O₄ (MH⁺): calcd, 438.1578; found, 438.1549.

EXAMPLE 135 N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

5(R)-3-[4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one

To a solution of 4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-benzyloxycarbonylaminobenzene (551 mg) in dry tetrahydrofuran (20 mL) was added a solution of t-butoxylithium in tetrahydrofuran (1.0 M, 2.0 mL) at room temperature, and the mixture was stirred for 15 min. (R)-Glycidyl butyrate (0.25 mL) was added to the mixture, the mixture was stirred at room temperature for 1 hour, and then at 50° C. for 3 hours. After quenching the reaction by the addition of methanol, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Treatment of the residue with ethyl acetate gave 5(R)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (284 mg).

MS (EI⁺) m/z: 389 (M⁺).

HRMS (EI⁺) for C₂₀H₂₇N₃O₅ (M⁺): calcd, 389.1951; found, 389.1924.

Step 2.

5(R)-5-Acetoxymethyl-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one.

To a solution of 5(R)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (3.34 g) in pyridine (20 mL) was added acetic anhydride (10 mL), the mixture was stirred at room temperature for 2 hours, and then concentrated in vacuo. Treatment of the residue with ethyl acetate gave 5(R)-5-acetoxymethyl-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl) amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one (3.19 g).

MS (EI⁺) m/z: 431 (M⁺).

HRMS (EI⁺) for C₂₂H₂₉N₃O₆ (M⁺): calcd, 431.2056; found, 431.2059.

Step 3.

N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a suspension of 5(R)-5-acetoxymethyl-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one (1.00 g) in methanol (100 mL) was added potassium carbonate (1.60 g), the mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. A suspension of the residue in tetrahydrofuran (100 mL) was added triethylamine (0.5 mL) and methanesulfonyl chloride (0.25 mL) at 0° C., and the mixture was stirred at the same temperature for 30 min. After dilution of the mixture with water, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo to give 5(R)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-methanesulfonyloxymethyloxazolidin-2-one (827 mg). The mixture of 5(R)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-5-methanesulfonyloxymethyloxazolidin-2-one (820 mg) and sodium azide (281 mg) in N,N-dimethylformamide (14 mL) was heated at 70° C. for 4 hours. After dilution of the mixture with water, the mixture was extracted with dichloromethane. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The crude 5(R)-azidomethyl-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]oxazolidin-2-one thus obtained was converted to N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (591 mg) according to the same manner as described for EXAMPLE 9.

MS (EI⁺) m/z: 430 (M⁺).

HRMS (EI⁺) for C₂₂H₃₀N₄O₅ (M⁺): calcd, 430.2216; found, 430.2219.

Step 4.

N-[5(S)-3-[4-[(1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (192 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (300 mg) in the same manner as described for EXAMPLE 64.

MS (EI⁺) m/z: 330 (M⁺).

HRMS (EI⁺) for C₁₇H₂₂N₄O₃ (M⁺): calcd, 330.1692; found, 330.1725.

EXAMPLE 136 N-[5(S)-3-[4-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The mixture of N-[5(S)-3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (1.08 g), (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (1.50 g), tetrakis(triphenylphosphine)palladium (173 mg) and 2 M sodium carbonate solution (4.5 mL) in dioxane (30 mL) was stirred at 80° C. for 2 hours. After dilution of the mixture with water, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=9:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. To a solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenyl silyl)oxy]methylbicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide thus obtained in tetrahydrofuran (20 mL) was added acetic acid (810 μL) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 9 mL) at room temperature, and the mixture was stirred at room temperature for 2 days. After dilution of the mixture with saturated sodium hydrogencarbonate solution, sodium chloride and water, the mixture was extracted with ethyl acetate-tetrahydrofuran (1:1). The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=8:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5ylmethyl]acetamide (953 mg).

MS (EI⁺) m/z: 342 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂N₂O₄ (M⁺): calcd, 342.1580; found, 342.1596.

EXAMPLE 137 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(Hydroxyimino)methyl]bicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-[(hydroxyimino) methyl]bicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (390 mg) was prepared from N-[5(S)-2-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (680 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 356 (MH⁺).

HRMS (FAB⁺) for C₁₉H₂₂N₃O₄ (MH⁺): calcd, 356.1610; found, 356.1576.

EXAMPLE 138 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-cyano bicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (188 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-[(hydroxyimino)methyl]bicyclo[3.1.0]hex-2-en-2-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (250 mg) in the same manner as described for EXAMPLE 49.

MS (EI⁺) m/z: 337 (M⁺).

HRMS (EI⁺) for C₁₉H₁₉N₃O₃ (M⁺): calcd, 337.1426; found, 337.1451.

EXAMPLE 139 N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-Butyldiphenylsilyl) oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The mixture of 5(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (739 mg), (1α,5α,6β)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-[(trifluoromethanesulfonyl)oxy]bicyclo[3.1.0]hex-2-ene (971 mg), tetrakis(triphenylphosphine)palladium (233 mg) and 2 M potasium phosphate solution (4.89 mL) in dioxane (24 mL) was stirred at 80° C. for 1.5 hours, and concentrated in vacuo after the insoluble materials were filtered off. Flash chromatography (silica, ethyl acetate:acetone=10:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6β)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (1.29 g).

MS (FAB⁺) m/z: 598 (MH⁺).

HRMS (FAB⁺) for C₃₅H₃₉FN₂O₄Si (MH⁺): calcd, 598.2663; found, 598.2627.

Step 2.

N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6β)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3-fluoro-4-[(1α,5α,6β)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (509 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6β)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (1.29 g) in the same manner as described for EXAMPLE 48.

MS (EI⁺) m/z: 360 (M⁺).

HRMS (EI⁺) for C₁₉H₂₁FN₂O₄ (M⁺): calcd, 360.1485; found, 360.1464.

EXAMPLE 140 N-[5(S)-3-[4-[(1α,5α,6β)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

To a suspension of N-[5(S)-3-[3-fluoro-4-[(1α,5α,6β)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (360 mg), N-methylmorpholine N-oxide (181 mg) and molecular sieves 4A (powdered, 500 mg) in dichloromethane (10 mL) and acetonitrile (1 mL) was added tetrapropylammonium perruthenate (36 mg) at room temperature, the resulting mixture was stirred for 35 min. After insoluble materials were filtered off, the filtrate was concentrated in vacuo to give N-[5(S)-3-[3-fluoro-4-[(1α,5α,6β)-6-formylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide. This was used in the next step without further purification. A suspension of crude N-[5(S)-3-[3-fluoro-4-[(1α,5α,6β)-6-formylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide thus obtained in methanol (5 mL) was added N,N-dimethylhydrazine (110 μL), and the mixture was stirred at room temperature for 20 min. To a suspension of magnesium monoperoxyphthalate hexahydrate (1.18 g) in methanol (6 mL) was added the above mixture at 0° C., and the mixture was stirred at the same temperature for 15 min. After addition of ice water to the mixture, the resulting precipitates were collected by filtration, washed with water, and then dried in air. Flash chromatography (silica, dichloromethane:methanol=5:1) of the precipitates gave N-[5(S)-3-[4-[(1α,5α,6β)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (231 mg).

MS (FAB⁺) m/z: 356 (MH⁺).

HRMS (FAB⁺) for C₁₉H₁₉FN₃O₃ (MH⁺): calcd, 356.1410; found, 356.1391.

EXAMPLE 141 N-[5(S)-3-[4-[(1α,5α,6β)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

Step 1.

N-[5(S)-3-[4-[(1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound N-[5(S)-3-[4-[(1α,5α,6β)-6-[(t-butyldiphenylsilyl) oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (929 mg) was prepared from N-[5(S)-3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (929 mg), (1α,5α,6β)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (1.17 g) and 2 M potassium phosphate solution (3.69 mL) instead of 2 M sodium carbonate solution in the same manner as described for EXAMPLE 136.

MS (FAB⁺) m/z: 580 (M⁺).

HRMS (FAB⁺) for C₃₅H₄₀N₂O₄Si (M⁺): calcd, 580.2757; found, 580.2763.

Step 2.

N-[5(S)-3-[4-[(1α,5α,6β)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6β)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (503 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6β)-6-[(t-butyldiphenylsilyl) oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (981 mg) in the same manner as described for EXAMPLE 48.

MS (EI⁺) m/z: 342 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂N₂O₄ (M⁺): calcd, 342.1580; found, 342.1557.

EXAMPLE 142 N-[5(S)-3-[4-[(1α,5α,6β)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[4-[(1α,5α,6β)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide was prepared from N-[5(S)-3-[4-[(1α,5α,6β)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (239 mg) in the same manner as described for EXAMPLE 140.

MS (EI⁺) m/z: 337 (M⁺).

HRMS (EI⁺) for C₁₉H₁₉N₃O₃ (M⁺): calcd, 337.1426; found, 337.1451.

EXAMPLE 143 N-[5(S)-3-[4-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer A)

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer A, 270 mg) was prepared from N-[5(S)-3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (902 mg) and (1α,5α,6α)-6-hydroxymethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (enantiomer A, >99% ee, 563 mg) in the same manner as described for EXAMPLE 136.

MS (EI⁺) m/z: 342 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂N₂O₄ (M⁺): calcd, 342.1580; found, 342.1596.

EXAMPLE 144 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer A)

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer A, 205 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer A, 266 mg) in the same manner as described for EXAMPLE 49.

MS (EI⁺) m/z: 337 (M⁺).

HRMS (EI⁺) for C₁₉H₁₉N₃O₃ (M⁺): calcd, 337.1426; found, 337.1401.

EXAMPLE 145 N-[5(S)-3-[4-[(1α,5α,6α)-6-Hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer B)

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]ex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer B, 282 mg) was prepared from N-[5(S)-3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (541 mg) and (1α,5α,6α)-6-hydroxymethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (enantiomer B, 94.4% ee, 338 mg) in the same manner as described for EXAMPLE 136.

MS (EI⁺) m/z: 342 (M⁺).

HRMS (EI⁺) for C₁₉H₂₂N₂O₄ (M⁺): calcd, 342.1580; found, 342.1572.

EXAMPLE 146 N-[5(S)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer B)

The title compound N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer B, 115 mg) was prepared from N-[5(S)-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (diastereomer B, 278 mg) in the same manner as described for EXAMPLE 49.

MS (EI⁺) m/z: 337 (M⁺).

HRMS (EI⁺) for C₁₉H₁₉N₃O₃ (M⁺): calcd, 337.1426; found, 337.1452.

EXAMPLE 147 N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-Cyano-2-dimethylamino)ethen-1-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

A solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-cyanomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (242 mg) and t-butoxybis(dimethylamino)methane (210 μL) in dimethylformamide (1.3 mL) was stirred at 90° C. for 9 hours. Flash chromatography (silica, ethyl acetate:methanol=4:1) of the mixture gave N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-cyano-2-dimethylamino)ethen-1-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (254 mg).

MS (EI⁺) m/z: 427 (M⁺).

EXAMPLE 148 N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-Amino-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

A solution of N-[5(S)-3-[4-[(1α,5α,6α)-6-[(1-cyano-2-dimethylamino)ethen-1-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (107 mg), hydrazine hydrate (37.5 mg) and acetic acid (14 μL) in ethanol (1 mL) was stirred at 80° C. for 7 hours, and then concentrated in vacuo. Preparative thin layer chromatography (silica, dichloromethane:methanol=5:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-(3-amino-1H-pyrazole-4-yl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (35.0 mg).

MS (FAB⁺) m/z: 415 (MH⁺).

HRMS (FAB⁺) for C₂₀H₂₄FN₆O₃ (MH⁺): calcd, 415.1894; found, 415.1919.

PREPARATIVE EXAMPLE 1 4-[(1α,5α,6α)-6-(N-t-Butoxycarbonylamino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene

To a suspension of (1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexane (2.97 g) and ethyldiisopropylamine (2.87 mL) in acetonitrile (17 mL) was added 3,4-difluoronitrobenzene (1.66 mL), and the mixture was stirred at 50° C. for 4.5 hours. After cooling, the resulting precipitates were collected by filtration, and then dried in vacuo to give 4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene (2.81 g). The filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, water, aqueous sodium hydrogencarbonate solution and brine, successively. The organic extracts were dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was treated with hexane and ethyl acetate, and the resulting precipitates were collected by filtration, and then dried in vacuo to give the additional product (1.38 g). The filtrate was concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=10:7) of the residue gave the additional product (228 mg).

¹H NMR (CDCl₃) δ 1.46 (s, 9H), 1.90 (s, 2H), 2.41 (s, 1H), 3.63

d, J=9.5 Hz, 2H), 3.92 (d, J=9.5 Hz, 2H), 6.52 (t, J=9.0 Hz, 1H), 7.85 (dd, J=14.2, 2.4 Hz, 1H), 7.91 (dd, J=9.0, 2.4 Hz, 1H).

MS (FAB⁺) m/z: 338 (MH⁺).

PREPARATIVE EXAMPLE 2 4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene.

To a solution of 4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene in N,N-dimethylformamide (89 mL) was added sodium hydride (689 mg), and the mixture was stirred at room temperature for 20 min, and then at 40° C. for 5 min. To the resulting solution were added benzyl chloride (1.75 mL) and tetrabutylammonium bromide (42.7 mg), and the mixture was stirred at 50° C. for 1 hour, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=5:2) of the residue gave 4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene (5.19 g).

¹H NMR (CDCl₃) δ 1.49 (s, 9H), 2.01 (s, 2H), 2.27 (s, 1H), 3.62 (d, J=9.3 Hz, 2H), 3.80-3.90 (m, 2H), 4.46 (s, 2H), 6.46 (t, J=9.0 Hz, 1H), 7.20-7.40 (m, 5H), 7.83 (dd, J=14.4, 2.7 Hz, 1H), 7.89 (dd, J=9.0, 2.7 Hz, 1H).

MS (FAB⁺) m/z: 428 (MH⁺).

PREPARATIVE EXAMPLE 3 4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo [3.1.0]hexan-3-yl]-1-benzyloxycarbonylamino-3-fluorobenzene.

A suspension of 4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene (5.19 g) and palladium catalyst (10% on charcoal, 519 mg) in ethyl acetate (52 mL) was hydrogenated at 1 atm for 2 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give 1-amino-4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorobenzene. This was used in the next step without further purification. To a solution of crude 1-amino-4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorobenzene thus obtained in acetone (48 mL) were successively added sodium hydrogencarbonate (1.12 g), water (11 mL) and benzyl chloroformate (2.01 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min. The mixture was diluted with ethyl acetate, washed with brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=5:2) of the residue gave 4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-benzyloxycarbonylamino-3-fluorobenzene (6.73 g).

¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.80-1.90 (m, 2H), 2.40-2.60 (m, 1H), 3.24 (d, J=8.5 Hz, 2H), 3.50-3.80 (m, 2H), 4.45 (s, 2H), 5.17 (s, 2H), 6.40-6.60 (m, 1H), 6.80-6.90 (m, 1H), 7.10-7.50 (m, 11H).

MS (EI⁺) m/z: 531 (M⁺).

PREPARATIVE EXAMPLE 4 Benzyl (1α,5α,6α)-6-[(2-Tetrahydropyranyl)oxy]methyl-3-azabicyclo [3.1.0]hexan-3-ylcarboxylate.

To a solution of benzyl (1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (1.00 g) and 3,4-dihydro-2H-pyran (0.37 mL) in dichloromethane (10 mL) was added p-toluenesulfonic acid (10.0 mg), and the mixture was stirred at room temperature for 3.5 hours. The mixture was washed with saturated sodium hydrogencarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:1) of the residue gave benzyl (1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (1.24 g).

PREPARATIVE EXAMPLE 5 Benzyl (1α,5α,6α)-6-Methoxymethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate

To a suspension of sodium hydride (178 mg, 60% oil dispersion) in tetrahydrofuran (7 mL) was added a solution of benzyl(1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (1.00 g) in tetrahydrofuran (3 mL) at 0° C. After stirring the mixture at the same temperature for 10 min, the mixture was treated with methyl iodide (0.28 mL) and stirred at room temperature for 2 hours, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, the resulting solution was washed with water, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:1) of the residue gave benzyl (1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (909 mg).

¹H NMR (CDCl₃) δ 0.91-0.96 (m, 1H), 1.44-1.49 (m, 2H), 3.20-3.24 (m, 1H), 3.31-3.35 (m, 1H), 3.33 (s, 3H), 3.41-3.46 (m, 2H), 3.67 (d, J=10.7 Hz, 1H), 3.70 (d, J=10.7 Hz, ¹H), 5.10 (s, 2H), 7.29-7.36 (m, 5H).

PREPARATIVE EXAMPLE 6 (1α,5α,6α-6-[(2-Tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexane.

A suspension of benzyl (1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (1.22 g) and palladium catalyst (10% on charcoal, 120 mg) in ethanol (12 mL) was hydrogenated at 1 atm for 2 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give (1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexane (699 mg).

PREPARATIVE EXAMPLE 7 (1α,5α,6α)-6-Methoxymethyl-3-azabicyclo[3.1.0]hexane.

The title compound (1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexane (238 mg) was prepared from benzyl (1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (900 mg) in the same manner as described for PREPARATIVE EXAMPLE 6.

¹H NMR (CDCl₃) δ 0.86-0.91 (m, 1H), 1.33-1.37 (m, 2H), 2.88 (d, J=11.2 Hz, 2H), 3.01 (d, J=11.7 Hz, 2H), 3.28 (d, J=7.3 Hz, 2H), 3.34 (s, 3H).

PREPARATIVE EXAMPLE 8 3-Fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene.

The title compound 3-fluoro-4-[(1α,5α,6α-6-[(2-tetrahydropyranyl) oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene (1.03 g) was prepared from (1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexane (690 mg) and 3,4-difluoronitrobenzene (0.39 mL) in the same manner as described for PREPARATIVE EXAMPLE 1.

PREPARATIVE EXAMPLE 9 3-Fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene

The title compound 3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene (421 mg) was prepared from (1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexane (230 mg) and 3,4-difluoronitrobenzene (0.20 mL) in the same manner as described for PREPARATIVE EXAMPLE 1.

¹H NMR (CDCl₃) δ 1.06-1.11 (m, 1H), 1.65-1.69 (m, 2H), 3.32 (d, J=6.8 Hz, 2H), 3.36 (s, 3H), 3.58-3.61 (m, 2H), 3.87 (dd, J=10.3, 3.4 Hz, 2H), 6.53 (t, J=8.8 Hz, 1H), 7.85 (dd, J=14.2, 2.2 Hz, 1H), 7.91 (dd, J=8.8, 2.4 Hz, 1H).

PREPARATIVE EXAMPLE 10 1-Amino-3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene.

The title compound 1-amino-3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (926 mg) was prepared from 3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo [3.1.0]hexan-3-yl]nitrobenzene (1.03 g) in the same manner as described for PREPARATIVE EXAMPLE 3.

MS (EI⁺) m/z: 306 (M⁺).

HRMS (EI⁺) for C₁₇H₂₃FN₂O₂ (M⁺): calcd, 306.1744; found, 306.1738.

PREPARATIVE EXAMPLE 11 1-Amino-3-fluoro-4-[(1α,5α,6α) -6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene.

The title compound 1-amino-3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (360 mg) was prepared from 3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene (416 mg) in the same manner as described for PREPARATIVE EXAMPLE 3.

¹H NMR (CDCl₃) δ 1.36-1.41 (m, 1H), 1.45-1.50 (m, 2H), 3.09 (d, J=8.8 Hz, 2H), 3.29 (d, J=6.8 Hz, 2H), 3.33-3.47 (br, 2H), 3.35 (s, 3H), 3.61 (dd, J=8.8, 2.4 Hz, 2H), 6.35-6.43 (m, 2H), 6.53 (t, J=8.3 Hz, 1H).

PREPARATIVE EXAMPLE 12 1-Benzyloxycarbonylamino-3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene.

The title compound 1-benzyloxycarbonylamino-3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (1.12 g) was prepared from 1-amino-3-fluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (915 mg) in the same manner as described for PREPARATIVE EXAMPLE 3.

MS (EI⁺) m/z: 440 (M⁺).

HRMS (EI⁺) for C₂₅H₂₉FN₂O₄ (M⁺): calcd, 440.2111; found, 440.2097.

PREPARATIVE EXAMPLE 13 1-Benzyloxycarbonylamino-3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene.

The title compound 1-benzyloxycarbonylamino-3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (539 mg) was prepared from 1-amino-3-fluoro-4-[(1α,5α,6α)-6-methoxymethyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (350 mg) in the same manner as described for PREPARATIVE EXAMPLE 3.

PREPARATIVE EXAMPLE 14 (1α,5α,6α)-6-[(t-Butyldiphenylsiyl)oxy]methylbicyclo[3.1.0]hex-2-ene.

To a solution of (1α,5α,6α)-bicyclo[3.1.0]hex-2-en-6-methanol (11.0 mg) in dichloromethane (0.4 mL) was added t-butyldiphenylsilyl chloride (32 μL), triethylamine (35 μL), and 4-(dimethylamino)pyridine (24.4 mg), and the mixture was stirred at room temperature for 3 hours. After quenching the reaction by the addition of 1 N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic extracts were washed with water, sodium hydrogencarbonate solution, and brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=50:1) of the residue gave (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-ene (28.3 mg).

¹H NMR (CDCl₃) δ 0.47-0.52 (m, 1H), 1.05 (s, 9H), 1.40-1.43 (m, 1H), 1.67-1.69 (m, 1H), 2.27-2.32 (m, 1H), 2.50-2.60 (m, 1H), 3.50-3.60 (m, 2H), 5.37-5.39 (m, 1H), 5.80-5.90 (m, 1H), 7.36-7.44 (m, 6H), 7.67-7.69 (m, 4H).

MS (EI⁺) m/z: 348 (M⁺).

PREPARATIVE EXAMPLE 15 (1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methyl-3-hydroxybicyclo[3.1.0]hexane Isomer A and B

To a solution of (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo [3.1.0]hex-2-ene (2.79 g) in tetrahydrofuran (28 mL) was added borane-methyl sulfide complex (927 μL) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. The resulting solution was added water (22 mL), 2.5 N sodium hydroxide solution (4.8 mL), and hydrogen peroxide solution (30%, 1.36 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. After dilution the mixture with water, the resulting mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=2:1) of the residue gave the two isomers of (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-hydroxybicyclo[3.1.0]hexane (2.38 g).

Isomer A

¹H NMR (CDCl₃) δ 0.70-0.75 (m, 1H), 1.03 (s, 9H), 1.00-1.70 (m, 4H), 2.11 (dd, J=12.7, 6.8 Hz, 2H), 3.43 (d, J=6.4 Hz, 2H), 3.90-4.00 (m, 1H), 7.36-7.44 (m, 6H), 7.65-7.70 (m, 4H).

MS (CI⁺) m/z: 367 (MH⁺).

Isomer B

¹H NMR (CDCl₃) δ1.04 (s, 9H), 1.00-1.10 (m, 2H), 1.26-1.31 (m, 1H), 1.68 (d, J=14.2 Hz, 2H), 2.00-2.10 (m, 2H), 3.51 (d, J=6.4 Hz, 2H), 4.35 (t, J=6.4 Hz, 1H), 7.35-7.44 (m, 6H), 7.66-7.70 (m, 4H).

MS (CI⁺) m/z: 367 (MH⁺).

PREPARATIVE EXAMPLE 16 (1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methyl-3-oxobicyclo[3.1.0]hexane.

To a solution of (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-hydroxybicyclo[3.1.0]hexane (2.38 g) in dimethyl sulfoxide (24 mL) was added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (2.73 g), and the mixture was stirred at room temperature for 5.5 hours. After addition of ethyl acetate and water, insoluble materials were filtered off. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane ethyl acetate 5:1) of the mixture gave (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-oxobicyclo[3.1.0]hexane (1.82 g).

¹H NMR (CDCl₃) δ 0.60-0.65 (m, 1H), 1.04 (s, 9H), 1.38-1.40 (m, 2H), 2.14 (dd, J=18.6, 2.0 Hz, 2H), 2.50-2.60 (m, 2H), 3.62 (d, J=5.9 Hz, 2H), 7.40-7.50 (m, 6H), 7.65-7.68 (m, 4H).

MS (EI⁺) m/z: 364 (M⁺).

PREPARATIVE EXAMPLE 17 (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-[(trifluoromethanesulfonyl)-oxy]bicyclo[3.1.0]hex-2-ene.

To a solution of (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-oxobicyclo[3.1.0]hexane (365 mg) in tetrahydrofuran (2 mL) was added a solution of lithium diisopropylamide (2M, 650 μL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. The resulting mixture was added a solution of N-phenylbis(trifluoromethanesulfonimide) (393 mg) in tetrahydrofuran (2 mL) at −78° C., the mixture was stirred at room temperature for 17 hours, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=25:1) of the residue gave (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-[(trifluoromethanesulfonyl)oxy]bicyclo[3.1.0]hex-2-ene (313 mg).

¹H NMR (CDCl₃) δ 077-0.82 (m, 1H), 1.04 (s, 9H), 1.30-1.50 (m, 1H), 1.60-1.70 (m, ¹H), 2.48-2.53 (m, 1H), 2.79-2.85 (m, 1H), 3.50-3.60 (m, 2H), 5.78-5.79 (m, 1H), 7.40-7.50 (m, 6H), 7.60-7.70 (m, 4H).

PREPARATIVE EXAMPLE 18 (1α,5α,6α)-6-[(t-Butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-ene.

To a solution of (1α,5α,6α)-bicyclo[3.1.0]hex-2-en-6-carboxylic acid (1.52 g) in dichloromethane (30 mL) were added triethylamine (1.87 mL) and ethyl chloroformate (1.32 mL) at 0° C., the mixture was stirred at the same temperature for 10 minutes, and then concentrated in vacuo. After dilution the resulting residue with acetone (15 mL), a solution of sodium azide (1.59 g) in water (8 mL) was added at 0° C., and the mixture was stirred at the same temperature for 10 minutes. After dilution the mixture with ice water, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The resulting residue was diluted with toluene (30 mL) and t-butanol (4.5 mL), the mixture was heated at reflux for 28 hours, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=10:3) of the residue gave (1α,5α,6α)-6-[(t-butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-ene (1.61 g).

¹H NMR (CDCl₃) δ 1.45 (s, 9H), 1.66 (t, J=6.9 Hz, 1H), 1.86 (brs, 1H), 2.01-2.04 (m, 1H), 2.42 (d, J=17.6 Hz, 1H), 2.59 (dd, J=17.6, 6.9 Hz, 1H), 5.46-5.49 (m, 1H), 5.80-5.90 (m, 1H).

MS (EI⁺) m/z: 195 (M⁺).

PREPARATIVE EXAMPLE 19 (1α,5α,6α)-6-[(t-Butoxycarbonyl)amino]-3-hydroxybicyclo[3.1.0]hex-2

To a solution of (1α,5α,6α)-6-[(t-butoxycarbonyl)amino]bicyclo [3.1.0]hex-2-ene (335 mg) in tetrahydrofuran (5 mL) was added borane-methyl sulfide complex (199 μL) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. The resulting solution was added water (3 mL), 2.5 N sodium hydroxide solution (1.03 mL), and hydrogen peroxide solution (30%, 292 μL) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. After dilution the mixture with ice water, the resulting mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Recrystallization with acetonitrile of the residue gave (1α,5α,6α)-6-[(t-butoxycarbonyl)amino]-3-hydroxybicyclo[3.1.0]hex-2-ene (146 mg). Flash chromatography (silica, hexane:ethyl acetate=2:1) of the residue gave further amount of (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-hydroxybicyclo[3.1.0]hexane (128 mg).

¹H NMR (CDCl₃) δ 1.43 (s, 9H), 1.30-1.80 (m, 4H), 2.10-2.20 (m, 3H), 3.90-4.00 (m, 1H)

MS (CI⁺) m/z: 214 (MH⁺).

PREPARATIVE EXAMPLE 20 (1α,5α,6α)-6-[(t-Butoxycarbonyl)amino]-3-oxobicyclo[3.1.0]hexane.

To a solution of (1α,5α,6α)-6-[(t-butoxycarbonyl)amino]-3-hydroxybicyclo[3.1.0]hex-2-ene (265 mg) in dimethyl sulfoxide (3 mL) was added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (521 mg), and the mixture was stirred at room temperature for 9 hours. After addition of ethyl acetate and water, insoluble materials were filtered off. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=5:1) of the residue gave (1α,5α,6α)-6-[(t-butoxycarbonyl)amino]-3-oxobicyclo[3.1.0]hexane (209 mg).

¹H NMR (CDCl₃) δ 1.45 (s, 9H), 1.72 (m, 2H), 2.09 (brs, 1H), 2.29 (d, J=20.1 Hz, 2H), 2.58-2.65 (m, 2H).

MS (FAB⁺) m/z: 212 (MH⁺).

PREPARATIVE EXAMPLE 21 (1α,5α,6α)-6-[Bis(t-butoxycarbonyl)amino]-3-oxobicyclo[3.1.0]hexane.

To a solution of (1α,5α,6α)-6-[(t-butoxycarbonyl)amino]-3-oxobicyclo [3.1.0]hexane (917 mg) and di-t-butyl dicarbonate (1.89 g) in dichloromethane (4 mL) and acetonitrile (4 mL) was added 4-(dimethylamino)pyridine (212 mg), the mixture was stirred at room temperature for overnight, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=2:1) of the residue gave (1α,5α,6α)-6-[bis(t-butoxycarbonyl)amino]-3-oxobicyclo[3.1.0]hexane (1.10 g).

¹H NMR (CDCl₃) δ 1.51 (s, 18H), 1.82-1.84 (m, 2H), 2.09-2.10 (m, 1H), 2.29-2.34 (m, 2H), 2.60-2.70 (m, 2H).

MS (FAB⁺) m/z: 312 (MH⁺).

PREPARATIVE EXAMPLE 22 (1α,5α,6α)-6-[Bis(t-butoxycarbonyl)amino]-3-[(trifluoromethanesulfonyl)-oxy]bicyclo[3.1.0]hex-2-ene.

To a solution of (1α,5α,6α)-6-[bis(t-butoxycarbonyl)amino]-3-oxobicyclo[3.1.0]hexane (1.10 g) in tetrahydrofuran (6 mL) was added a solution of lithium diisopropylamide (2M, 2.30 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. The resulting mixture was added a solution of N-phenylbis(trifluoromethanesulfonimide) (1.33 g) in tetrahydrofuran (7 mL) at −78° C., the mixture was stirred at room temperature for 17 hours, and then concentrated in vacuo. Flash chromatography (silica, hexane:acetone=5:1) of the residue gave (1α,5α,6α)-6-[bis(t-butoxycarbonyl)amino]-3-[(trifluoromethane sulfonyl)oxy]-bicyclo[3.1.0]hex-2-ene (1.30 g).

¹H NMR (CDCl₃) δ 1.52 (s, 18H), 1.76-1.80 (m, 1H), 2.00-2.20 (m, 1H), 2.19-2.20 (m, 1H), 2.68-2.72 (m, 1H), 2.90-3.00 (m, 1H), 5.04 (m, 1H).

MS (FAB⁺) m/z: 444 (MH⁺).

PREPARATIVE EXAMPLE 23 Benzyl (1α,5α,6α)-6-Formyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate.

The title compound benzyl (1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (168 mg) was prepared from benzyl (1α,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (196 mg) in the same manner as described for EXAMPLE 22.

MS (EI⁺) m/z: 245 (M⁺).

HRMS (EI⁺) for C₁₄H₁₅NO₃ (M⁺): calcd, 245.1052; found, 245.1034.

PREPARATIVE EXAMPLE 24 Benzyl (1α,5α,6α)-6-Acetyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate.

Step 1.

Benzyl (1α,5α,6α)-6-(1-hydroxy)ethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate

To a solution of benzyl (1α,5α,6α)-6-formyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (45 mg) in tetrahydrofuran (2 mL) was added methyl magnesiumbromide (3 M solution in diethylether, 122 μL) at 0° C., and the mixture was stirred at room temperature for 2 hours. After quenching the reaction by the addition of saturated ammonium chloride solution, the mixture was exrtacted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo to give benzyl (1α,5α,6α)-6-(1-hydroxy)ethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate.

Step 2.

Benzyl (1α,5α,6α)-6-acetyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate

The title compound benzyl (1α,5α,6α)-6-acetyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (34.0 mg) was prepared from the above crude benzyl (1α,5α,6α)-6-(1-hydroxy)ethyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate in the same manner as described for EXAMPLE 22.

MS (EI⁺) m/z: 259 (M⁺).

HRMS (EI⁺) for C₁₅I₁₇NO₃(M⁺): calcd, 259.1208; found, 259.1199.

PREPARATIVE EXAMPLE 25 Benzyl (1α,5α,6α)-6-Hydroxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate.

Step 1.

Benzyl (1α,5α,6α)-6-acetoxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate.

To a solution of benzyl (1α,5α,6α)-6-acetyl-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (23.0 mg) in dichloromethane (1 mL) was added urea-hydrogen peroxide complex (83.0 mg) and trifluoroacetic anhydride (100 μL) at 0° C., and the mixture was stirred at room temperature for 18 hours. After quenching the reaction by the addition of saturated sodium hydrogencarbonate solution and 5% sodium thiosulfate solution, the mixture was exrtacted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, and then concentrated in vacuo to give benzyl (1α,5α,6α)-6-acetoxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate.

Step 2.

Benzyl (1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate.

To a solution of the above crude benzyl (1α,5α,6α)-6-acetoxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate in methanol (2 mL) was added potassium carbonate (13.8 mg), and the mixture was stirred at room temperature for 10 min, and then concentrated in vacuo. After addition of water to the residue, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:1) of the residue gave benzyl (1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (6.3 mg).

MS (EI⁺) m/z: 233 (M⁺).

HRMS (EI⁺) for C₁₃H₁₅NO₃ (M⁺): calcd, 233.1052; found, 233.1067.

PREPARATIVE EXAMPLE 26 Benzyl (1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate

To a solution of benzyl (1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (610 mg) in dichloromethane was added imidazole (267 mg) and t-butyldimethylsilyl chloride (434 mg) at 0° C., and the mixture was stirred at room temperature for 1 hour. The mixture was washed with water, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=85:15) of the residue gave benzyl (1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (800 mg).

MS (FAB⁺) m/z: 348 (MH⁺).

HRMS (FAB⁺) for C₁₉H₃₀NO₃Si (MH⁺): calcd, 348.1995; found, 348.1989.

PREPARATIVE EXAMPLE 27 4-[(1α,5α,6α)-6-t-Butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene

Step 1.

(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexane.

The title compound (1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexane was prepared from benzyl (1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-ylcarboxylate (780 mg) in the same manner as described for PREPARATIVE EXAMPLE 6.

MS (FAB⁺) m/z: 214 (MH⁺).

HRMS (FAB⁺) for C₁₁H₂₄NOSi (MH⁺): calcd, 214.1627; found, 214.1628.

Step 2.

4-[(1α,5α,6α)-6-t-Butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene and 4-[(1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene

The title compounds 4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluoronitrobenzene (87 mg) and 4-[(1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene (270 mg) were prepared from the above crude (1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexane and 3,4-difluoronitrobenzene (392 mg) in the same manner as described for PREPARATIVE EXAMPLE 1.

Step 3.

4-[(1α,5α,6α)-6-t-Butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene

The title compound 4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluoronitrobenzene (379 mg) was prepared from 4-[(1α,5α,6α)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene (270 mg) in the same manner as described for PREPARATIVE EXAMPLE 26.

MS (FAB⁺) m/z: 353 (MH⁺).

HRMS (FAB⁺) for C₁₇H₂₆FN₂O₃Si (MH⁺): calcd, 353.1697; found, 353.1669.

PREPARATIVE EXAMPLE 28 1-Benzyloxycarbonylamino-4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorobenzene.

The title compound 1-benzyloxycarbonylamino-4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorobenzene (342 mg) was prepared from 4-[(1α,5α,6α)-6-t-butyldimethylsilyloxy-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoronitrobenzene (379 mg) in the same manner as described for PREPARATIVE EXAMPLE 3.

MS (EI⁺) m/z: 322 (M⁺).

HRMS (EI⁺) for C₁₇H₂₇FN₂OSi (M⁺): calcd, 322.1877; found, 322.1869.

PREPARATIVE EXAMPLE 29 4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluoronitrobenzene.

The title compound 4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluoronitrobenzene (4.59 g) was prepared from (1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexane (3.50 g) and 3,4,5-trifluoronitrobenzene (3.20 g) in the same manner as described for PREPARATIVE EXAMPLE 1.

MS (EI⁺) m/z: 355 (M⁺).

HRMS (EI⁺) for C₁₆H₁₉F₂N₃O₄ (M⁺): calcd, 355.1344; found, 355.1357.

PREPARATIVE EXAMPLE 30 4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluoronitrobenzene.

The title compound 4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluoronitrobenzene (4.40 g) was prepared from 4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluoronitrobenzene (4.11 g) in the same manner as described for PREPARATIVE EXAMPLE 2.

¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.92 (s, 2H), 2.31 (s, 1H), 3.73-3.90 (m, 4H), 4.45 (s, 2H), 7.23-7.68 (m, 7H).

PREPARATIVE EXAMPLE 31 4-[(1α,5α,6α)-6-(N-Benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-benzyloxycarbonylamino-3,5-difluorobenzene.

The title compound 4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-benzyloxycarbonylamino-3,5-difluorobenzene (4.72 g) was prepared from 4-[(1α,5α,6α)-6-(N-benzyl-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-3,5-difluoronitrobenzene (4.40 g) in the same manner as described for PREPARATIVE EXAMPLE 3.

MS (FAB⁺) m/z: 550 (MH⁺).

HRMS (FAB⁺) for C₃₁H₃₄F₂N₃O₄ (MH⁺): calcd, 550.2517; found, 550.2507.

PREPARATIVE EXAMPLE 32 3,5-Difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene.

The title compound 3,5-difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl) oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene (5.82 g) was prepared from (1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexane (6.50 g) and 3,4,5-trifluoronitrobenzene (3.92 g) in the same manner as described for PREPARATIVE EXAMPLE 1.

MS (EI⁺) m/z: 354 (M⁺)

HRMS (EI⁺) for C₁₇H₂₀F₂N₂O₄(M⁺): calcd, 354.1391; found, 354.1422.

PREPARATIVE EXAMPLE 33 1-Benzyloxycarbonylamino-3,5-difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene.

The title compound 1-benzyloxycarbonylamino-3,5-difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl)oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]benzene (7.50 g) was prepared from 3,5-difluoro-4-[(1α,5α,6α)-6-[(2-tetrahydropyranyl) oxy]methyl-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene (5.79 g) in the same manner as described for PREPARATIVE EXAMPLE 3.

MS (EI⁺) m/z: 424 (M⁺).

HRMS (EI⁺) for C₁₇H₂₀F₂N₂O₄ (M⁺): calcd, 424.1810; found, 424.1848.

PREPARATIVE EXAMPLE 34 5(R)-3-(3-Fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one

Step 1.

5(R)-Acetoxymethyl-3-(3-fluorophenyl)oxazolidin-2-one

To a solution of 5(R)-3-(3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (5.28 g) in tetrahydrofuran (53 mL) was added triethylamine (3.83 mL), acetic anhydride (2.55 mL) and (4-dimethylamino)pyridine (152 mg), and the mixture was stirred at room temperature for 1 hour. After quenching the reaction by the addition of 1 N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give crude 5(R)-acetoxymethyl-3-(3-fluorophenyl)oxazolidin-2-one (6.33 g).

Step 2.

5(R)-Acetoxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one

To a solution of 5(R)-acetoxymethyl-3-(3-fluorophenyl)oxazolidin-2-one (6.33 g) in acetic acid (40 mL) was added iodine monochloride (1.91 mL), the mixture was stirred at room temperature for 18 hours, and then concentrated in vacuo. The resulting residue was dissolved with ethyl acetate, the mixture was washed with aqueous sodium hydrogencarbonate solution. 20% sodium sulfite solution and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give crude 5(R)-acetoxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (9.48 g).

Step 3.

5(R)-3-(3-Fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one

To a solution of crude 5(R)-acetoxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (9.48 g) in methanol (95 mL) was added potassium carbonate (6.91 g), and the mixture was stirred at room temperature for 2.5 hours. After insoluble materials were filtered off, the filtrate was concentrated in vacuo. The residue was dissoluved with ethyl acetate, the mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. After treating of the residue with isopropanol, the resulting precipitates were collected by filtration to give 5(R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one, and the filtrate was concentrated in vacuo. Flash chromatography (silica, ethyl acetate) of the residue gave further amount of the product (total 6.24 g).

MS (EI⁺) nt/z: 337 (M⁺).

¹H NMR (CDCl₃) δ2.15 (t, J=6.4 Hz, 1H), 3.74-4.80 (m, 5H), 7.07 (dd, J=8.8, 2.4 Hz, 1H), 7.48 (dd, J=10.3, 2.4 Hz, 1H), 7.70 (dd, J=8.8, 6.8 Hz, 1H).

PREPARATIVE EXAMPLE 35 5(R)-3-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-5-hydroxymethyloxazolidin-2-one

A suspension of 5(R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one (674 mg), pinacoldiboron (570 mg), potassium acetate (982 mg), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (163 mg) in dimethyl sulfoxide (13 mL) was heated at 80° C. for 2 hours. After dilution the mixture with aqueous ammonium chloride solution, the mixture was extracted ethyl acetate. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:5) of the residue gave 5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-5-hydroxymethyloxazolidin-2-one (529 mg).

MS (EI⁺) m/z: 337 (M⁺).

¹H NMR (CDCl₃) δ 1.36 (s, 12H), 2.22 (br, 1H), 3.76-4.79 (m, 5H), 7.29-7.74 (m, 3H).

PREPARATIVE EXAMPLE 36 5(R)-Acetoxymethyl-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl) oxy]methyl bicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]oxazolidin-2-one.

Step 1.

5(R)-3-[4-[(1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl) oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-hydroxy methyloxazolidin-2-one (523 mg) was prepared from 5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-5-hydroxymethyloxazolidin-2-one (344 mg) and (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-3-[(trifluoromethanesulfonyl)oxy]bicyclo[3.1.0]hex-2-ene (507 mg) in the same manner as described for EXAMPLE 88.

MS (EI⁺) m/z: 557 (M⁺).

¹H NMR (CDCl₃) δ 0.74 (m, 1H), 1.05 (s, 9H), 1.52-2.09 (m, 3H), 2.69-4.78 (m, 9H), 6.46 (s, 1H), 7.15-7.70 (m, 13H).

Step 2.

5(R)-Acetoxymethyl-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]oxazolidin-2-one.

The title compound 5(R)-acetoxymethyl-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]oxazolidin-2-one (939 mg) was prepared from 5(R)-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl) oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (959 mg) in the same manner as described for PREPARATIVE EXAMPLE 34.

MS (FAB⁺) m/z: 600 (MH⁺).

¹H NMR (CDCl₃) δ 0.75 (m, 1H), 1.05 (s, 9H), 1.53-2.05 (m, 2H), 2.10 (s, 3H), 2.69-4.89 (m, 9H), 6.47 (d, J=2.0 Hz, 1H), 7.15-7.70 (m, 13H).

PREPARATIVE EXAMPLE 37 5(R)-Acetoxymethyl-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethylbicyclo [3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one.

The title compound 5(R)-acetoxymethyl-3-[3-fluoro4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (444 mg) was prepared from 5(R)-acetoxymethyl-3-[4-[(1α,5α,6α)-6-[(t-butyldiphenylsilyl) oxy]methylbicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]oxazolidin-2-one (878 mg) in the same manner as described for EXAMPLE 48.

MS (EI⁺) m/z: 361 (M⁺).

¹H NMR (CDCl₃) δ 0.82 (m, 1H), 1.28-1.99 (m, 3H), 2.10 (s, 3H), 2.76-4.90 (m, 9H), 6.50 (t, 5=2.0 Hz, 1H), 7.16-7.41 (m, 3H).

PREPARATIVE EXAMPLE 38 5(R)-Acetoxymethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]oxazolidin-2-one

The title compound 5(R)-acetoxymethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo [3.1.0]hex-2-en-3-yl]-3-fluorophenyl]oxazolidin-2-one (436 mg) was prepared from 5(R)-acetoxymethyl-3-[3-fluoro-4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]nex-2-en-3-yl]phenyl]oxazolidin-2-one (442 mg) in the same manner as described for EXAMPLE 49.

MS (EI⁺) m/z: 356 (M⁺).

¹H NMR (CDCl₃) δ 1.29 (t, J=3.4 Hz, 1H), 2.02 (s, 3H), 2.39-3.12 (m, 4H), 3.80-4.96 (m, 5H), 6.14 (s, 1H), 7.27-7.52 (m, 3H).

PREPARATIVE EXAMPLE 39 5(R)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one

The title compound 5(R)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (178 mg) was prepared from 5(R)-acetoxymethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]-3-fluorophenyl]oxazolidin-2-one (436 mg) in the same manner as described for PREPARATIVE EXAMPLE 34.

MS (EI⁺) m/z: 314 (M⁺).

¹H NMR (DMSO-d6) δ 1.30 (t, J=3.4 Hz, 1H), 2.38-3.13 (m, 4H), 3.51-5.23 (m, 6H), 6.41 (s, 1H), 7.28-7.54 (m, 3H).

PREPARATIVE EXAMPLE 40 4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene

The title compound 4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene (10.04 g) was prepared from (1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexane (9.76 g) and 4-fluoronitrobenzene (5.7 mL) in the same manner as described for PREPARATIVE EXAMPLE 1.

MS (EI⁺) m/z: 319 (M⁺).

HRMS (EI⁺) for C₁₆H₂₁N₃O₄ (M⁺): calcd, 319.1532; found, 319.1501.

PREPARATIVE EXAMPLE 41 4-[(1α,5α,6α)-6-(N-t-Butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-benzyloxycarbonylaminobenzene

The title compound 4-[(1α,5α,6α)-6-(N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-benzyloxycarbonylaminobenzene (10.60 g) was prepared from 4-[(1α,5α,6α)-6-N-t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-3-yl]nitrobenzene (8.88 g) in the same manner as described for PREPARATIVE EXAMPLE 3.

MS (EI⁺) m/z: 423 (M⁺).

HRMS (EI⁺) for C₂₄H₂₉N₃O₄ ((M⁺)): calcd, 423.2158; found, 423.2139.

PREPARATIVE EXAMPLE 42 5(R)-5-Acetoxymethyl-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one.

The title compound 5(R)-5-acetoxymethyl-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (2.81 g) was prepared from 5(R)-5-acetoxymethyl-3-[4-[(1α,5α,6α)-6-(t-butyldiphenylsilyl)oxy methylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (5.10 g) in the same manner as described for EXAMPLE 48.

MS (EI⁺) m/z: 343 (M⁺).

HRMS (EI⁺) for C₁₉H₂₁NO₅ (M⁺): calcd, 343.1420; found, 343.1404.

PREPARATIVE EXAMPLE 43 5(R)-5-Acetoxymethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one

The title compound 5(R)-5-acetoxymethyl-3-[4-[(1α,5α,6α)-6-cyano bicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (2.20 g) was prepared from 5(R)-5-acetoxymethyl-3-[4-[(1α,5α,6α)-6-hydroxymethylbicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (2.60 g) in the same manner as described for EXAMPLE 49.

MS (EI⁺) m/z: 338 (M⁺).

HRMS (EI⁺) for C₁₉H₁₈N₂O₄ (M⁺): calcd, 338.1267; found, 338.1260.

PREPARATIVE EXAMPLE 44 5(R)-3-[4-[(1α,5α,6α)-6-Cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one

To a suspension of 5(R)-5-acetoxymethyl-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]oxazolidin-2-one (1.93 g) in methanol was added potassium carbonate (788 mg), the mixture was stirred at room temperature for 10 min, and then concentrated in vacuo. After addition of water and 5% hydrochloric acid to the residue, the resulting mixture extracted with dichloromethane. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Treatment of the residue with ethyl acetate gave 5(R)-3-[4-[(1α,5α,6α)-6-cyanobicyclo[3.1.0]hex-2-en-3-yl]phenyl]-5-hydroxymethyloxazolidin-2-one (1.60 g).

MS (EI⁺) m/z: 296 (M⁺).

HRMS (EI⁺) for C₁₇H₁₆N₂O₃ (M⁺): calcd, 296.1161; found, 296.1148.

PREPARATIVE EXAMPLE 45 (1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methyl-2-oxobicyclo[3.1.0]hexane.

To a solution of (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methylbicyclo [3.1.0]hex-2-ene (10.00 g) in tetrahydrofuran (80 mL) was added borane-methyl sulfide complex (3.33 mL) under ice water cooling, and the mixture was stirred at room temperature for 1.5 hours. The resulting solution was added water (58 mL), 2.5 N sodium hydroxide solution (17.2 mL), and hydrogen peroxide solution (30%, 4.88 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. After dilution the mixture with ice water, the resulting mixture was extracted with ether. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. To a solution of chromium oxide (5.74 g) in pyridine (57 mL) was added a solution of the above residue in pyridine (10 mL) at 0° C., and the mixture was stirred at room temperature for 12 hours. After addition of ethyl acetate to the mixture, insoluble materials were filtered off, and then concentrated in vacuo. The ethereal solution of the residue was washed with 1 N hydrochloric acid, water, aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=4:1) of the precipitates gave (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-oxobicyclo[3.1.0]hexane (935 mg).

MS (CI) m/z: 365 (MH⁺).

HRMS (CI) for C₂₃H₂₉O₂Si (MH⁺): calcd, 365.1937; found, 365.1947.

PREPARATIVE EXAMPLE 46 (1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methyl-2-[(trifluoromethanesulfonyl)oxy]bicyclo[3.1.0]hex-2-ene.

The title compound (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-[(trifluoromethanesulfonyl)oxy]bicyclo[3.1.0]hex-2-ene (5.20 g) was prepared from (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-oxobicyclo[3.1.0]hexane (4.65 g) in the same manner as described for PREPARATIVE EXAMPLE 17.

MS (CI) m/z: 497 (MH⁺).

HRMS (CI) for C₂₄H₂₈F₃O₄SSi (MH⁺): calcd, 497.1430; found, 497.1441.

PREPARATIVE EXAMPLE 47 (1α,5α,6α)-6-[(t-Butyldiphenylsilyl)oxy]methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene.

The mixture of (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-[(trifluoromethanesulfonyl)oxy]bicyclo[3.1.0]hex-2-ene (5.20 g), pinacoldiboron (2.93 g), potassium phenoxide (2.08 g), bis(triphenylphosphine)dichloropalladium (367 mg) and triphenylphosphine (275 mg) in toluene (100 mL) was stirred at 50° C. for 12 hours, and then concentrated in vacuo after insoluble materials were filtered off. Flash chromatography (silica, hexane:ether=9:1) of the precipitates gave (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (3.15 g).

MS (CI) m/z: 475 (MH⁺).

HRMS (CI) for C₂₉H₄₀BO₃Si (MH⁺): calcd, 475.2840; found, 475.2842.

PREPARATIVE EXAMPLE 48 N-[5(S)-3-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

The title compound N-[5(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (758 mg) was prepared from N-[5(S)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (1.13 g) and pinacoldiboron (855 mg) in the same manner as described for PREPARATIVE EXAMPLE 35.

MS (EI⁺) m/z: 378 (M⁺).

HRMS (EI⁺) for C₁₈C₂₄BFN₂O₅ (M⁺): calcd, 378.1762; found, 378.1786.

PREPARATIVE EXAMPLE 49 (1α,5α,6β)-6-[(t-Butyldiphenylsilyl)oxy]methyl-2-(4,4,5,5-tetramethyl-1,3,2-ioxaborolyl)bicyclo[3.1.0]hex-2-ene.

The title compound (1α,5α,6β)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene was prepared from (1α,5α,6β)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-[(trifluoromethanesulfonyl)oxy]bicyclo [3.1.0]hex-2-ene (124 mg) in the same manner as described for PREPARATIVE EXAMPLE 47.

MS (EI⁺) m/z: 474 (M⁺).

HRMS (EI⁺) for C₂₉H₃₉BO₃Si ((M⁺)): calcd, 474.2762; found, 474.2799.

PREPARATIVE EXAMPLE 50 (1α,5α,6α)-6-hydroxymethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl) bicyclo[3.1.0]hex-2-ene.

To a solution of (1α,5α,6α)-6-[(t-butyldiphenylsilyl)oxy]methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (4.00 g) in methanol (50 mL) was added a solution of 2 M HCl in ether, the mixture was stirred at 60° C. for 20 min, and then concentrated in vacuo. The mixture of the above residue, anhydrous magnesium sulfate (10.10 g) and pinacol (1.99 g) in toluene (50 mL) was stirred at 80° C. for 30 min. After the insoluble Materials were filtered off, the mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=2:1) of the residue gave (1α,5α,6α)-6-hydroxymethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)bicyclo[3.1.0]hex-2-ene (1.40 g). Optical resolution of this compound was performed by HPLC using CHIRALPAK AS (hexane:2-propanol=50:1, RT=24.2 min and 26.7 min).

MS (CI) m/z: 237 (MH⁺).

HRMS (CI) for C₁₃H₂₂BO₃ (MH⁺): calcd, 237.1662; found, 237.1682.

The invention has been described herein with reference to certain preferred embodiments. However, as obvious variations thereon will become apparent to those of skill in the art, the invention is not to be considered as limited thereto. 

1. A compound of the following formula I:

its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof wherein: A represents C (when --- is present), CH, or N (when --- is not present); — ---- represents a bond; R represents hydrogen, or C₁₋₆ alkyl; R₁ and R₂ independently represent i) hydrogen, ii) NR₅R₆, iii) CR₇R₈R₉, C(R)₂OR₁₄ CH₂NH₁₄, iv) C(═O)R₁₃, C(═NOH)H, C(═NOR₁₃)H, C(═NOR₁₃)R₁₃, C(═NOH)R₁₃, C(═O)N(R₁₃)₂, C(═NOH)N(R₁₃)₂, NHC(═X₁)N(R₁₃)₂, (C═NH)R₇, N(R₁₃)C(═X₁)N(R₁₃)₂, COOR₁₃, SO₂R₁₄, N(R₁₃)SO₂R₁₄, N(R₁₃)COR₁₄, or (C₁₋₆alkyl)CN, CN, CH═C(R)₂, OH, C(═O)CHR₁₃, C(═NR₁₃)R₁₃, NHC(═X₁)R₁₃; v)

vi) C₅₋₁₀ heterocycle optionally substituted with 1-3 groups of R₇, which may be attached through either a carbon or a heteroatom;

represents heterocycle, heterocyclyl or heterocyclic, Rx represents hydrogen or C₁₋₆ alkyl; R₃ represent i) NH(C═X₂)R₁₂, ii) NHSO₂R₁₄, iii) NH(CH₂)₀₋₄aryl, iv) NH(CH₂)₀₋₄heteroaryl, v) S(CH₂)₀₋₄aryl, vi) S(CH₂)₀₋₄heteroaryl, vii) O(CH₂)₀₋₄aryl, or viii) O(CH₂)₀₋₄heteroaryl; R₄ and R_(4a) independently represent i) hydrogen, ii) halogen, iii) C₁₋₆ alkoxy, or iv) C₁₋₆ alkyl r and s independently are 1-3, with the provision that when (R_(4a))_(s) and (R₄)_(r) are attached to an Ar or HAr ring the sum of r and s is less than or equal to 4; R₅ and R₆ independently represent i) hydrogen, ii) C₁₋₆ alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C₁₋₆ alkoxy, amino, imino, hydroxyamino, alkoxyamino, C₁₋₆ acyloxy, C₁₋₆ alkylsulfenyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, C₁₋₆ dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethylenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF₃, C₁₋₆ alkyl or C₁₋₆ alkoxy; iii) C₁₋₆ acyl optionally substituted with 1-3 groups of halogen, OH, SH, C₁₋₆ alkoxy, naphthalenoxy, phenoxy, amino, C₁₋₆ acylamino, hydroxylamino, alkoxylamino, C₁₋₆ acyloxy, aralkyloxy, phenyl, pyridine, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ hydroxyacyloxy, C₁₋₆ alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3-groups of halo, OH, CN, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl; iv) C₁₋₆ alkylsulfonyl optionally substituted with 1-3 groups of halogen, OH, C₁₋₆ alkoxy, amino, hydroxylamino, alkoxylamino, C₁₋₆ acyloxy, or phenyl; said phenyl optionally substituted with 1-3 groups of halo, OH, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl; v) arylsulfonyl optionally substituted with 1-3 of halogen, C₁₋₆ alkoxy, OH or C₁₋₆ alkyl; vi) C₁₋₆ alkoxycarbonyl optionally substituted with 1-3 of halogen, OH, C₁₋₆ alkoxy, C₁₋₆ acyloxy, or phenyl, said phenyl optionally substituted with 1-3 groups of halo, OH, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl; vii) aminocarbonyl, C₁₋₆ alkylaminocarbonyl or C₁₋₆ dialkylaminocarbonyl, said alkyl groups optionally substituted with 1-3 groups of halogen, OH, C₁₋₆ alkoxy or phenyl; viii) five to six membered heterocycles optionally substituted with 1-3 groups of halogen, OH, CN, amino, C₁₋₆ acylamino, C₁₋₆ alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkoxy, C₁₋₆ acyloxy or C₁₋₆ alkyl, said alkyl optionally substituted with 1-3 groups of halogen, or C₁₋₆ alkoxy; ix) C₃₋₆ cycloalkylcarbonyl optionally substituted with 1-3 groups of halogen, OH, C₁₋₆ alkoxy or CN; x) benzoyl optionally substituted with 1-3 groups of halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl, CF₃, C₁₋₆ alkanoyl, amino or C₁₋₆ acylamino; xi) pyrrolylcarbonyl optionally substituted with 1-3 of C₁₋₆ alkyl; xii) C₁₋₂ acyloxyacetyl where the acyl is optionally substituted with amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl; or R₅ and R₆ taken together with any intervening atoms can form a 3 to 7 membered heterocyclic ring containing 1-2 heteroatoms independently chosen from O, S, SO, SO₂, N, or NR₈; R₇ represent i) hydrogen, halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl, alkenyl, ii) amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, hydroxylamino or C₁₋₂ alkoxyamino all of which can be optionally substituted on the nitrogen with C₁₋₆ acyl, C₁₋₆ alkylsulfonyl or C₁₋₆ alkoxycarbonyl, said acyl and alkylsulfonyl optionally substituted with 1-2 of halogen or OH; R₈ and R₉ independently represents i) H, CN, ii) C₁₋₆ alkyl optionally substituted with 1-3 halogen, CN, OH, C₁₋₆ alkoxy, C₁₋₆ acyloxy, or amino, iii) phenyl optionally substituted with 1-3 groups of halogen, OH, C₁₋₆ alkoxy; or R₇ and R₈ taken together can form a 3-7 membered ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO₂, NH, and NR₈; X₁ represents O, S or NR₁₃, NCN, or NSO₂R₁₄; X₂ represents O, S, NH or NSO₂R₁₄; R₁₀ represents hydrogen, C₁₋₆ alkyl or CO₂R₁₅; R₁₁ represents hydrogen, C₁₋₆ alkyl, C₁₋₆ alkanoyl, halogen, amino, C₁₋₆ acylamino, C₁₋₆ alkoxy, OH or CF₃, NHC₁₋₆ alkyl, or N(C₁₋₆ alkyl)₂, where said alkyl may be substituted with 1-3 groups of halo, OH or C₁₋₆ alkoxy; R₁₂ represents hydrogen, C₁₋₆ alkyl, NH₂, C₁₋₆ alkylamino, C₁₋₆ alkoxy or C₁₋₆ dialkylamino, where said alkyl may be substituted with 1-3 groups of halo, OH or C₁₋₆ alkoxy; Each R₁₃ represents independently hydrogen, C₁₋₆ alkyl, NR₅R₆, SR₈, S(O)R₈, S(O)₂R₈, CN, C₁₋₆ alkylS(O)R, C₁₋₆ alkoxycarbonyl, hydroxycarbonyl, C₁₋₆ acyl, C₃₋₇ membered carbon ring optionally interrupted with 1-4 heteroatoms chosen from O, S, SO, SO₂, NH and NR₈ where said C₁₋₆ alkyl or C₁₋₆ acyl groups may be independently substituted with 0-3 halogens, hydroxy, N(R)₂, CO₂R, C₆₋₁₀aryl, C₅₋₁₀heteroaryl, or C₁₋₆alkoxy groups; When two R₁₃ groups are attached to the same atom or two adjacent atoms they may be taken together to form a 3-7 membered ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO₂, NH, and NR₈; R₁₄ represents amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, five to six membered heterocycles or phenyl, said phenyl and heterocycles optionally substituted with 1-3 group of halo, C₁₋₆ alkoxy, C₁₋₆ acylamino, or C₁₋₆ alkyl, hydroxy and/or amino, s aid amino and hydroxy optionally protected with an amino or hydroxy protecting group; R₁₅ is C₁₋₆ alkyl or benzyl said benzyl optionally substituted with 1-3 groups of halo, OH, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, or C₁₋₆ alkyl; and m, n, and q represents 0-1.
 2. A compound according to claim 1 wherein A is CH.
 3. A compound according to claim 1 wherein A is C and --- is present.
 4. A compound according to claim 1 wherein A is N.
 5. A compound according to claim 1 wherein R₁ and R₂ independently represent H, NR₅R₆, CN, OH, C(R)₂OR₁₄, NHC(═X1)N(R₁₃)₂, C(═NOH)N(R₁₃)₂, or CR₇R₈R₉.
 6. A compound according to claim 1 wherein

is pyridine, pyrimidine, or piperidine.
 7. A compound according to claim 5 wherein one of R₁ and R₂ is H and the other is NR₅R₆.
 8. A compound according to claim 5 wherein one of R₁ and R₂ is H and the other is CN.
 9. A compound according to claim 1 wherein R₅ and R₆ independently are: i) hydrogen, ii) C₁₋₆ alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C₁₋₆ alkoxy, amino, imino, hydroxyamino, alkoxyamino, C₁₋₆ acyloxy, C₁₋₆ alkylsulfenyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, C₁₋₆ dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethyenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF₃, C₁₋₆ alkyl or C₁₋₆ alkoxy; iii) C₁₋₆ acyl optionally substituted with 1-3 groups of halogen, OH, SH, C₁₋₆ alkoxy, naphthalenoxy, phenoxy, amino, C₁₋₆ acylamino, hydroxylamino, alkoxylamino, C₁₋₆ acyloxy, aralkyloxy, phenyl, pyridine, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ hydroxyacyloxy, C₁₋₆ alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3 groups of halo, OH, CN, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl; iv) benzoyl optionally substituted with 1-3 groups of halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl, CF₃, C₁₋₆ alkanoyl, amino or C₁₋₆ acylamino.
 10. A compound according to claim 1 wherein X₁ represents O.
 11. A compound according to claim 1 wherein one of R₁ or R₂ is hydrogen and the other is:

wherein R₁₀, X₁, m, q, and R₁₁ are as described in claim
 1. 12-19. (canceled)
 20. A compound according to claim 1 of the structural formula IIIa or IIIb:

wherein R₁, R₂, R₃, R₄, R_(4a), and Rx are as described in claim 1 and A is N.
 21. A compound according to claim 20 wherein R₁ and R₂ independently represent H, NR₅R₆, CN, OH, C(R)₂OR₁₄, NHC(═X1)N(R₁₃)₂, C(═NOH)N(R₁₃)₂, or CR₇R₈R₉


22. A compound according to claim 21 wherein one of R₁ and R₂ is H and the other is NR₅R₆.
 23. A compound according to claim 21 wherein one of R₁ and R₂ is H and the other is CN.
 24. A compound according to claim 1 of the structural formula IIIa or IIIb:

wherein R₁, R₂, R₃, R₄, R_(4a), and Rx are as described herein and A is C wherein --- is present.
 25. A compound according to claim 24 wherein R₁ and R₂ independently represent H, NR₅R₆, CN, OH, C(R)₂OR₁₄, NHC(═X1)N(R₁₃)₂, C(═NOH)N(R₁₃)₂, or CR₇R₈R₉


26. A compound according to claim 25 wherein one of R₁ and R₂ is H and the other is NR₅R₆.
 27. A compound according to claim 25 wherein one of R₁ and R₂ is H and the other is CN. 28-31. (canceled)
 32. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
 32. (canceled)
 33. A pharmaceutical composition produced by combining a compound in accordance with claim 1 with a pharmaceutically acceptable carrier.
 34. A method of treating or preventing a bacterial infection in a mammalian patient in need thereof, comprising administering to said patient an effective amount of a compound of claim
 1. 35. A method for the preparation of a compound of claim 1, wherein A is a nitrogen atom and the 3-azabicyclo[3.1.0]hexane has a 6-amino substituent, the method comprising: 1) reacting a 6-amino-3-azabicyclo[3.1.0]hexane having a protected 6-amino substituent with a heteroaryl compound bearing a nitro group and a leaving group; 2) reducing the product from step 1) to the corresponding amino compound, and protecting the resulting amino group; 3) reacting the protected amino heteroaryl product from step 2) with a strong base and then condensing with a glycidyl ester to form a 5-hydroxymethyloxazolidinone as a product; 4) converting the 5-hydroxymethyloxaxolidinone from step 3) to a 5-aminomethyloxazolidinone by first converting the hydroxy group to an activated leaving group, displacing the leaving group with sodium azide, and then reducing the resulting 5-azidooxazolidinone to the amine; and 5) acylating the 5-aminooxazolidinone from step 4) and converting the amino substituent to R₃.
 36. A method according to claim 35, wherein the product from step 5) is further subjected to reductive alkylation, or acylation.
 37. A method according to claim 35, wherein the protected amino heteroaryl product from step 2), after reaction with a strong base, is reacted with a racemic glycidyl ester to prepare a racemic oxazolidinone.
 38. A method according to claim 35, wherein the protected amino heteroaryl product from step 2), after reaction with a strong base, is reacted with a chiral glycidyl ester to prepare chiral oxazolidinone.
 39. A method according to claim 38, wherein the chiral glycidylester is an R-glycidylester.
 40. A method according to claim 38, wherein the chiral glycidylester is an S-glycidylester.
 41. A method for the preparation of a compound of claim 1, wherein A is a nitrogen atom and the 3-azabicyclo[3.1.0]hexane has a 6-carbon substituent, the method comprising: 1) reacting a 6-amino-3-azabicyclo[3.1.0]hexane having a protected 6-hydroxyl or 6-alkyl substituent with a heteroaryl compound bearing a nitro group and a leaving group; 2) reducing the product from step 1) to the corresponding amino compound, and protecting the resulting amino group; 3) reacting the protected amino heteroaryl product from step 2) with a strong base and then condensing with a glycidyl ester to form a 5-hydroxymethyloxazolidinone as a product; 4) converting the 5-hydroxymethyloxazolidinone from step 3) to a 5-aminomethyloxazolidinone by first converting the hydroxy group to an activated leaving group, displacing the leaving group with sodium azide, and then reducing the resulting 5-azidooxazolidinone to the amine; and 5) acylating the 5-aminooxazolidinone from step 4) and converting the amino substituent to R₃.
 42. A method according to claim 41, wherein the protected amino heteroaryl product from step 2), after reaction with a strong base, is reacted with a racemic glycidyl ester to prepare a racemic oxazolidinone.
 43. A method according to claim 41, wherein the protected amino heteroaryl product from step 2), after reaction with strong base, is reacted with a chiral glycidyl ester to prepare a chiral oxazolidinone.
 44. A method according to claim 43, wherein the chiral glycidylester is an R-glycidylester.
 45. A method according to claim 43, wherein the chiral glycidylester is an S-glycidylester.
 46. A method for preparation of a compound of claim 1, wherein the 3-azabicyclo[3.1.0]hexane has a protected hydroxyl group in the 6-position, the method comprising: 1) removing the protecting group to provide the free hydroxyl group; 2) activating the hydroxy group displacement with a nucleophilic substituent by converting the hydroxyl group to a leaving group; and 3) reacting the product from step 2) to replace the leaving group with a nucleophilic group.
 47. A method for preparation of a compound of claim 1, wherein the 3-azabicyclo-[3.1.0]hexane has a protected hydroxyl group in the 6-position, the method comprising: 1) removing the protecting group to provide the free hydroxyl group; 2) oxidizing the hydroxyl group to the aldehyde; 3) further oxidizing the aldehyde group to the carboxylic acid; and 4) converting the carboxylic acid to a leaving group and treating with a nucleophile to introduce a nucleophilic group into the 6-position.
 48. A method for the preparation of a compound of claim 1, wherein A contains a carbon atom and the 3-azabicyclo[3.1.0]hexane has a 6-amino substituent, the method comprising: 1) reacting a protected 3-trifluoromethanesulfonyl-6-amino-bicyclo[3.1.0]hexene with a substituted 2-oxo-3-(4-trimethylstannylphenyl)-5-substituted oxazolidinone to produce a cross-coupled product; and 2) reducing the double bond by hydrogenation to produce the bicylo[3.1.0]hexane. 